Thioether substituted imidazoquinolines

ABSTRACT

Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain thioether functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

[0001] This application is a continuation-in-part of Ser. No.10/013,059, filed Dec. 6, 2001 which claims the benefit of Ser. No.60/254,218, filed on Dec. 8, 2000.

FIELD OF THE INVENTION

[0002] This invention relates to imidazoquinoline compounds that havethioether functionality at the 1-position, and to pharmaceuticalcompositions containing such compounds. A further aspect of thisinvention relates to the use of these compounds as immunomodulators, forinducing cytokine biosynthesis in animals, and in the treatment ofdiseases, including viral and neoplastic diseases.

BACKGROUND OF THE INVENTION

[0003] The first reliable report on the 1H-imidazo[4,5-c]quinoline ringsystem, Backman et al., J. Org. Chem. 15, 1278-1284 (1950) describes thesynthesis of1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline forpossible use as an antimalarial agent. Subsequently, syntheses ofvarious substituted 1H-imidazo[4,5-c] quinolines were reported. Forexample, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesizedthe compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as apossible anticonvulsant and cardiovascular agent. Also, Baranov et al.,Chem. Abs. 85, 94362 (1976), have reported several2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic Chem.18, 1537-1540 (1981), have reported certain2-oxoimidazo[4,5-c]quinolines.

[0004] Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and2-substituted derivatives thereof were later found to be useful asantiviral agents, bronchodilators and immunomodulators. These aredescribed in, inter alia, U.S. Pat. Nos. 4,689,338; 4,698,348;4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640, all of whichare incorporated herein by reference.

[0005] There continues to be interest in the imidazoquinoline ringsystem.

[0006] Certain 1H-imidazo[4,5-c] naphthyridine-4-amines, 1H-imidazo[4,5-c] pyridin-4-amines, and 1H-imidazo[4,5-c] quinolin-4-amines havingan ether containing substituent at the 1 position are known. These aredescribed in U.S. Pat. Nos. 5,268,376; 5,389,640; 5,494,916; and WO99/29693.

[0007] Despite these attempts to identify compounds that are useful asimmune response modifiers, there is a continuing need for compounds thathave the ability to modulate the immune response, by induction ofcytokine biosynthesis or other mechanisms.

SUMMARY OF THE INVENTION

[0008] We have found a new class of compounds that are useful ininducing cytokine biosynthesis in animals. Accordingly, this inventionprovides imidazoquinoline-4-amine and tetrahydroimidazoquinoline-4-aminecompounds that have a thioether containing substituent at the1-position. The compounds are defined by Formulas (I) and (II), whichare defined in more detail infra. These compounds share the generalstructural formula:

[0009] wherein X, Z, R₁, R₂, and R are as defined herein for each classof compounds having Formulas (I) and (II).

[0010] The compounds of formulas (I) and (II) are useful as immuneresponse modifiers due to their ability to induce cytokine biosynthesisand otherwise modulate the immune response when administered to animals.This makes the compounds useful in the treatment of a variety ofconditions such as viral diseases and tumors that are responsive to suchchanges in the immune response.

[0011] The invention further provides pharmaceutical compositionscontaining the immune response modifying compounds, and methods ofinducing cytokine biosynthesis in an animal, treating a viral infectionin an animal, and/or treating a neoplastic disease in an animal byadministering a compound of Formula (I) or (II) to the animal.

[0012] In addition, the invention provides methods of synthesizing thecompounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0013] As mentioned earlier, we have found certain compounds that inducecytokine biosynthesis and modify the immune response in animals. Suchcompounds are represented by Formulas (I) and (II) as shown below.

[0014] Imidazoquinoline compounds of the invention, which have thioetherfunctionality at the 1-position are represented by Formula (I):

[0015] wherein: X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-;

[0016] Z is —S—, —SO—, or —SO₂—;

[0017] R₁ is selected from the group consisting of:

[0018] -alkyl;

[0019] -aryl;

[0020] -heteroaryl;

[0021] -heterocyclyl;

[0022] -alkenyl;

[0023] —R₄-aryl;

[0024] —R₄-heteroaryl;

[0025] —R₄-heterocyclyl;

[0026] —R₂ is selected from the group consisting of:

[0027] -hydrogen;

[0028] -alkyl;

[0029] -alkenyl;

[0030] -aryl;

[0031] -heteroaryl;

[0032] -heterocyclyl;

[0033] -alkyl-Y-alkyl;

[0034] -alkyl-Y-alkenyl;

[0035] -alkyl-Y-aryl; and

[0036] -alkyl or alkenyl substituted by one or more substituentsselected from the group consisting of:

[0037] —OH;

[0038] -halogen;

[0039] —N(R₃)₂;

[0040] —CO—N(R₃)₂;

[0041] —CO—C₁₋₁₀alkyl;

[0042] —CO—O—C₁₋₁₀alkyl;

[0043] —N₃;

[0044] -aryl;

[0045] -heteroaryl;

[0046] -heterocyclyl;

[0047] —CO-aryl; and

[0048] —CO-heteroaryl;

[0049] each R₃ is independently H or C-₁₋₁₀ alkyl;

[0050] R₄ is alkyl or alkenyl;

[0051] each Y is independently —O— or —S(O)₀₋₂—;

[0052] n is 0 to 4; and

[0053] each R present is independently selected from the groupconsisting of C₁₋₁₀

[0054] alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen and trifluoromethyl;

[0055] or a pharmaceutically acceptable salt thereof.

[0056] The invention also includes tetrahydroimidazoquinoline compoundsthat bear a thioether containing substituent at the 1-position. Suchtetrahydroimidazoquinoline compounds are represented by Formula (II):

[0057] wherein: X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-;

[0058] Z is —S—, —SO—, or —SO₂—;

[0059] R₁ is selected from the group consisting of:

[0060] -alkyl;

[0061] -aryl;

[0062] -heteroaryl;

[0063] -heterocyclyl;

[0064] -alkenyl;

[0065] —R₄-aryl;

[0066] —R₄-heteroaryl; and

[0067] —R₄-heterocyclyl;

[0068] R₂ is selected from the group consisting of:

[0069] -hydrogen;

[0070] -alkyl;

[0071] -alkenyl;

[0072] -aryl;

[0073] -heteroaryl;

[0074] -heterocyclyl;

[0075] -alkyl-Y-alkyl;

[0076] -alkyl-Y- alkenyl;

[0077] -alkyl-Y-aryl; and

[0078] -alkyl or alkenyl substituted by one or more substituentsselected from the group consisting of:

[0079] —OH;

[0080] -halogen;

[0081] —N(R₃)₂;

[0082] —CO-N(R₃)₂;

[0083] —CO—C₁₋₁₀ alkyl;

[0084] —CO—O—C₁₋₁₀ alkyl;

[0085] —N₃;

[0086] -aryl;

[0087] -heteroaryl;

[0088] -heterocyclyl;

[0089] —CO-aryl; and

[0090] —CO-heteroaryl;

[0091] each R₃ is independently H or C₁₋₁₀ alkyl;

[0092] R₄ is alkylene or alkenylene;

[0093] Y is —O—or —S(O)0-2—;

[0094] n is 0 to 4; and

[0095] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl;

[0096] or a pharmaceutically acceptable salt thereof.

Preparation of the Compounds

[0097] Compounds of the invention can be prepared according to ReactionScheme I where R, R₁, R₂, X and n are as defined above.

[0098] In step (1) of Reaction Scheme I a 4-chloro-3-nitroquinoline ofFormula X is reacted with an amine of formula HO—X—NH₂ to provide a3-nitroquinolin-4-amine of Formula XI. The reaction can be carried outby adding the amine to a solution of a compound of Formula X in asuitable solvent such as chloroform or dichloromethane in the presenceof triethylamine and optionally heating. Many quinolines of Formula Xare known compounds (see for example, U.S. Pat. No. 4,689,338 andreferences cited therein). Many amines of formula HO—X—NH₂ arecommercially available; others can be readily prepared using knownsynthetic routes.

[0099] In step (2) of Reaction Scheme I a 3-nitroquinolin-4-amine ofFormula XI is chlorinated to provide a 3-nitroquinolin-4-amine ofFormula XII. Conventional chlorinating agents can be used. Preferablythe reaction is carried out by combining a compound of Formula XI withthionyl chloride in a suitable solvent such as dichloromethane. Thereaction may be run at ambient temperature or it may be heated.Alternatively the reaction may be run neat.

[0100] In step (3) of Reaction Scheme I a 3-nitroquinolin-4-amine ofFormula XII is reduced to provide a quinoline-3,4-diamine of FormulaXIII. Preferably, the reduction is carried out using a conventionalheterogeneous hydrogenation catalyst such as platinum on carbon. Thereaction can conveniently be carried out on a Parr apparatus in asuitable solvent such as toluene.

[0101] In step (4) of Reaction Scheme I a quinoline-3,4-diamine ofFormula XIII is reacted with a carboxylic acid or an equivalent thereofto provide a 1H-imidazo[4,5-c]quinoline of Formula XIV. Suitableequivalents to a carboxylic acid include orthoesters, and1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent isselected such that it will provide the desired R₂ substituent in acompound of Formula XIV. For example, triethyl orthoformate will providea compound where R₂ is-hydrogen and trimethyl orthovalerate will providea compound where R₂ is butyl. The reaction can be run in the absence ofsolvent or in an inert solvent such as toluene. The reaction is run withsufficient heating to drive off any alcohol or water formed as abyproduct of the reaction. Optionally a catalyst such as pyridinehydrochloride can be included.

[0102] Alternatively, step (4) can be carried out by (i) reacting thediamine of Formula XIII with an acyl halide of Formula R₂C(O)Cl orR₂C(O)Br and then (ii) cyclizing. In part (i) the acyl halide is addedto a solution of the diamine in a suitable solvent such as pyridine. Thereaction can be carried out at ambient temperature. In part (ii) theproduct of part (i) is heated in pyridine in the presence of pyridinehydrochloride.

[0103] In step (5) of Reaction Scheme I a 1H-imidazo[4,5-c]quinoline ofFormula XIV is oxidized to provide a 1H-imidazo[4,5-c]quinoline-5N-oxideof Formula XV using a conventional oxidizing agent capable of formingN-oxides. Preferably a solution of a compound of Formula XIV in asuitable solvent such as chloroform or dichloromethane is treated with3-chloroperoxybenzoic acid at ambient temperature.

[0104] In step (6) of Reaction Scheme I a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XV is aminated to providea 1H-imidazo[4,5-c]quinolin-4-amine of Formula XVI. Step (6) involves(i) reacting a compound of Formula XV with an acylating agent and then(ii) reacting the product with an aminating agent. Part (i) of step (6)involves reacting an N-oxide of Formula XV with an acylating agent.Suitable acylating agents include alkyl- or arylsulfonyl chlorides(e.g., benezenesulfonyl chloride, methanesulfonyl chloride,p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred.Para-toluenesulfonyl chloride is most preferred. Part (ii) of step (6)involves reacting the product of part (i) with an excess of an aminatingagent. Suitable aminating agents include ammonia (e.g., in the form ofammonium hydroxide) and ammonium salts (e.g., ammonium carbonate,ammonium bicarbonate, ammonium phosphate). Ammonium hydroxide ispreferred. The reaction is preferably carried out by dissolving theN-oxide of Formula XV in an inert solvent such as dichloromethane orchloroform, adding the aminating agent to the solution, and then slowlyadding the acylating agent.

[0105] In step (7) of Reaction Scheme I a1H-imidazo[4,5-c]quinolin-4-amine of Formula XVI is reacted with acompound of Formula R₁—SNa to provide a1H-imidazo[4,5-c]quinolin-4-amine of Formula XVII which is a subgenus ofFormula I. The reaction can be carried out by combining a compound ofFormula XVI with a compound of formula R₁SNa in a suitable solvent suchas N,N-dimethylformamide or dimethyl sulfoxide. The reaction may be runat ambient temperature or it may be heated (60-80° C.). The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods.

[0106] In step (8) of Reaction Scheme I a1H-imidazo[4,5-c]quinolin-4-amine of Formula XVII is oxidized using aconventional oxidizing agent to provide a1H-imidazo[4,5-c]quinolin-4-amine of Formula XVIII which is a subgenusof Formula I. Preferably a solution of a compound of Formula XVII in asuitable solvent such as chloroform or dichloromethane is treated with3-chloroperoxybenzoic acid at ambient temperature. The degree ofoxidation is controlled by adjusting the amount of 3-chloroperoxybenzoicacid used in the reaction; i.e., using approximately one equivalent willprovide the sulfoxide whereas using two equivalents will provide thesulfone. The product or a pharmaceutically acceptable salt thereof canbe isolated using conventional methods.

[0107] Compounds of the invention can be prepared according to ReactionScheme II where R, R₁, R₂, X and n are as defined above.

[0108] In step (1) of Reaction Scheme II a 3-nitroquinolin-4-amine ofFormula XIII is reacted with a compound of the Formula R₁—SNa using themethod of step (7) of Reaction Scheme I to provide a3-nitroquinolin-4-amine of Formula XIX.

[0109] In step (2) of Reaction Scheme II a 3-nitroquinolin-4-amine ofFormula XIX is reduced using the method of step (3) of Reaction Scheme Ito provide a quinoline-3,4-diamine of Formula XX.

[0110] In step (3) of Reaction Scheme II a quinoline-3,4-diamine ofFormula XX is cyclized using the method of step (4) of Reaction Scheme Ito provide a 1H-imidazo[4,5-c]quinoline of Formula XXI.

[0111] In step (4) of Reaction Scheme II a 1H-imidazo[4,5-c]quinoline ofFormula XXI is oxidized to provide a 1H-imidazo[4,5-c]quinolin-5N-oxideof Formula XXII using a conventional oxidizing agent. Preferably asolution of a compound of Formula XXI in a suitable solvent such aschloroform or dichloromethane is treated with at least three equivalentsof 3-chloroperoxybenzoic acid at ambient temperature.

[0112] In step (5) of Reaction Scheme II a1H-imidazo[4,5-c]quinolin-5N-oxide of Formula XXII is aminated using themethod of step (6) of Reaction Scheme I to provide a1H-imidazo[4,5-c]quinolin-4-amine of Formula XVIII which is a subgenusof Formula I. The product or a pharmaceutically acceptable salt thereofcan be isolated using conventional methods.

[0113] Compounds of the invention can be prepared according to ReactionScheme III where R, R₁, R₂, X and n are as defined above.

[0114] In step (1) of Reaction Scheme III a3-nitro-4-amino-quinolin-1-yl alcohol of Formula XI is protected with atert-butyldimethylsilyl group using conventional methods. Preferably acompound of Formula XI is combined with tert-butyldimethylsilyl chloridein a suitable solvent such as chloroform in the presence oftriethylamine and a catalytic amount of 4-dimethylaminopyridine.

[0115] In step (2) of Reaction Scheme III a protected3-nitro-4-amino-quinolin-1-yl alcohol of Formula XXIII is reduced usingthe method of step (3) of Reaction Scheme I to provide a protected 3,4-diamino-quinolin-1-yl alcohol of Formula XXIV.

[0116] In step (3) of Reaction Scheme HI a protected3,4-diamino-quinolin-1-yl alcohol of Formula XXIV is cyclized using themethod of step (4) of Reaction Scheme I to provide a1H-imidazo[4,5-c]quinoline of Formula XXV.

[0117] In step (4) of Reaction Scheme III a 1H-imidazo[4,5-c]quinolineof Formula XXV is oxidized using the method of step (5) of ReactionScheme I to provide a 1H-imidazo[4,5-c]quinolin-5N-oxide of FormulaXXVI.

[0118] In step (5) of Reaction Scheme III a1H-imidazo[4,5-c]quinolin-5N-oxide of Formula XXVI is aminated using themethod of step (6) of Reaction Scheme I to provide a1H-imidazo[4,5-c]quinolin-4-amine of Formula XXVII.

[0119] In step (6) of Reaction Scheme III the protecting group isremoved from a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXVII toprovide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXVII. Preferablya solution of a compound of Formula XXVII in a suitable solvent such astetrahydrofuran is treated with tetrabutylammonium fluoride. Somecompounds of Formula XXVIII are known, see for example, Gerster, U.S.Pat. No. 4,689,338 and Gerster et al., U.S. Pat. No. 5,605,899.

[0120] In step (7) of Reaction Scheme III a1H-imidazo[4,5-c]quinolin-4-amine of Formula XXVIII is chlorinated usingconventional methods to provide a 1H-imidazo[4,5-c]quinolin-4-amine ofFormula XVI. A compound of Formula XXVIII can be heated neat withthionyl chloride. Alternatively, phosphorous oxychloride can be added ina controlled fashion to a solution of a compound of Formula XXVIII in asuitable solvent such as N,N-dimethylformamide in the presence oftriethylamine.

[0121] Steps (8) and (9) of Reaction Scheme III can be carried out inthe same manner as steps (7) and (8), respectively, of Reaction SchemeI.

[0122] Compounds of the invention can be prepared according to ReactionScheme IV where R, R₁, R₂, X and n are as defined above and BOC istert-butoxycarbonyl.

[0123] In step (1) of Reaction Scheme IV the hydroxy group of a6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl alcohol of FormulaXXIX is protected with a tert-butyldimethylsilyl group using the methodof step (1) of Reaction Scheme III. Compounds of Formula XXIX are knownor can be prepared using known synthetic methods, see for example,Nikolaides, et al., U.S. Pat. No.5,352,784 and Lindstrom, U.S. Pat. No.5,693,811 and references cited therein.

[0124] In step (2) of Reaction Scheme IV the amino group of a1H-imidazo[4,5-c]quinolin-4-amine of Formula XXX is protected usingconventional methods to provide a protected 1H-imidazo[4,5-c]quinolineof Formula XXXI. Preferably a compound of Formula XXX is treated withdi-tert-butyl dicarbonate in a suitable solvent such as tetrahydrofuranin the presence of triethylamine and 4-dimethylaminopyridine. Thereaction can be run at an elevated temperature (60° C.).

[0125] In step (3) of Reaction Scheme IV the tert-butyldimethylsilylprotecting group of a compound of Formula XXXI is removed using themethod of step (6) of Reaction Scheme III to provide a1H-imidazo[4,5-c]quinolin-1yl alcohol of Formula XXXII.

[0126] In step (4) of Reaction Scheme IV a 1H-imidazo[4,5-c]quinolin-1ylalcohol of Formula XXXII is converted to a methanesulfonate of FormulaXXXIII. Preferably a solution of a compound of Formula XXXII in asuitable solvent such as dichloromethane is treated with methanesulfonylchloride in the presence of triethylamine. The reaction can be run at areduced temperature (−10° C.).

[0127] In step (5) of Reaction Scheme IV a methanesulfonate of FormulaXXXIII is reacted with a thiol of formula RISH to provide a thioether ofFormula XXXIV. Preferably a solution of a compound of Formula XXXIII ina suitable solvent such as N, N-dimethylformamide is treated with thethiol in the presence of triethylamine. The reaction can be run at anelevated temperature (80° C.).

[0128] In step (6) of Reaction Scheme IV the tert-butoxycarbonylprotecting groups are removed by hydrolysis under acidic conditions toprovide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXV which is asubgenus of Formula II. Preferably a solution of a compound of FormulaXXXIV in a suitable solvent such as dichloromethane is treated atambient temperature with a solution of hydrochloric acid in dioxane. Theproduct or a pharmaceutically acceptable salt thereof can be isolatedusing conventional methods.

[0129] In step (7) of Reaction Scheme IV a thioether of Formula XXXV isoxidized using the method of step (8) of Reaction Scheme I to provide asulfone or sulfoxide of Formula XXXVI which is a subgenus of Formula II.The product or a pharmaceutically acceptable salt thereof can beisolated using conventional methods.

[0130] Compounds of the invention can be prepared according to ReactionScheme V where R, R₁, R₂, X and n are as defined above.

[0131] In step (1) of Reaction Scheme V a6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl alcohol of FormulaXXIX is chlorinated using the method of step (7) of Reaction Scheme IIIto provide a compound of Formula XXXVII.

[0132] In step (2) of Reaction Scheme V a compound of Formula XXXVII isreacted with a compound of formula R₁—SNa using the method of step (7)of Reaction Scheme I to provide a thioether of Formula XXXV which is asubgenus of Formula II. The product or a pharmaceutically acceptablesalt thereof can be isolated using conventional methods.

[0133] In step (3) of Reaction Scheme V a thioether of Formula XXXV isoxidized using the method of step (8) of Reaction Scheme I to provide asulfone or sulfoxide of Formula XXXVI which is a subgenus of Formula II.The product or a pharmaceutically acceptable salt thereof can beisolated using conventional methods.

[0134] Compounds of the invention can be prepared according to ReactionScheme VI where R, R₁, R₂, X, Z and n are as defined above.

[0135] In Reaction Scheme VI a 1H-imidazo[4,5-c]quinoline of Formula Iis reduced to provide a 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline ofFormula II. The reduction is carried out by dissolving a compound ofFormula I in trifluoroacetic acid, adding a catalytic amount of platinum(IV) oxide, then subjecting the mixture to hydrogen pressure. Thereaction can conveniently be carried out on a Parr apparatus. Theproduct or a pharmaceutically acceptable salt thereof can be isolatedusing conventional methods.

[0136] Compounds of the invention can be prepared according to ReactionScheme VII where R, R₁, R₂, X and n are as defined above and Ph isphenyl.

[0137] In step (1) of Reaction Scheme VII a2,4-dihydroxy-3-nitro-6,7,8,9-tetrahydroquinoline of Formula XXXVIII ischlorinated using conventional chlorinating agents to provide a2,4-dichloro-3-nitro-6,7,8,9-tetrahydroquinoline of Formula XXXIX.Preferably a compound of Formula XXXVIII is combined with phosphorousoxychloride and heated. Some2,4-dihydroxy-3-nitro-6,7,8,9-tetrahydroquinolines of Formula XXXVIIIare known and others can be prepared using known synthetic methods, seefor example, Nikolaides et al., U.S. Pat. No. 5,352,784 and thereferences cited therein.

[0138] In step (2) of Reaction Scheme VII, a2,4-dichloro-3-nitro-6,7,8,9-tetrahydroquinoline of Formula XXXIX isreacted with an amine of formula HO—X—NH₂ to provide a2-chloro-3-nitro-6,7,8,9-tetrahydroquinoline of Formula XXXX. Thereaction can be carried out by adding the amine to a solution of acompound of Formula XXXIX in a suitable solvent such asN,N-dimethylformamide in the presence of triethylamine and optionallyheating.

[0139] In step (3) of Reaction Scheme VII, a2-chloro-3-nitro-6,7,8,9-tetrahydroquinoline of Formula XXXX is reactedwith sodium phenoxide to provide a3-nitro-2-phenoxy-6,7,8,9-tetrahydroquinoline of Formula XXXXI. Phenolis reacted with sodium hydride in a suitable solvent such as1,2-dimethoxyethane to form the phenoxide. The phenoxide is then reactedat an elevated temperature with a compound of Formula XXXX.

[0140] In step (4) of Reaction Scheme VII, a3-nitro-2-phenoxy-6,7,8,9-tetrahydroquinoline of Formula XXXXI ischlorinated using conventional chlorinating agents to provide a3-nitro-2-phenoxy-6,7,8,9-tetrahydroquinoline of Formula XXXXII.Preferably N-chlorosuccinimide is reacted with triphenylphosphine in asuitable solvent such as tetrahydrofuran to form the phosphino chloride,which is then reacted with a compound of Formula XXXXI.

[0141] In Step (5) of Reaction Scheme VII, a3-nitro-2-phenoxy-6,7,8,9-tetrahydroquinoline of Formula XXXXII isreduced using conventional methods to provide a3-amino-2-phenoxy-6,7,8,9-tetrahydroquinoline of Formula XXXXIII. Apreferred method involves the in situ generation of Ni₂B. Sodiumborohydride is added to a mixture of nickel(II)chloride hexahydrate anda compound of Formula XXXXII in 50/50 methanol/chloroform.

[0142] In step (6) of Reaction Scheme VII, a3-amino-2-phenoxy-6,7,8,9-tetrahydroquinoline of Formula XXXXIII iscyclized using the method of step (4) of Reaction Scheme I to provide a4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline of Formula III.

[0143] In step (7) of Reaction Scheme VII, a4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline of Formula IIIis reacted with a compound of Formula R₁SNa to provide a4-phenoxy-6,7,8,9-tetrahydro-6,7,8,9-1H-imidazo[4,5-c]quinoline ofFormula XXXXIV which is a subgenus of Formula IV. Preferably a thiol ofthe Formula R₁SH is reacted with sodium hydride in a suitable solventsuch as N,N-dimethylformamide to generate the anion, which is thenreacted with a compound of Formula III.

[0144] In step (8a) of Reaction Scheme VII,4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline of FormulaXXXXIV is aminated to provide a6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-4-amine of Formula XXXVwhich is a subgenus of Formula II. The reaction can be carried out bycombining a compound of Formula XXXXIV with ammonium acetate and heating(−150° C.). Optionally, the reaction may be carried out in a pressurevessel. The product or a pharmaceutically acceptable salt thereof can beisolated using conventional methods.

[0145] In step (8b) of Reaction Scheme VII, a4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline of FormulaXXXXIV is oxidized using the method of step (8) of Reaction Scheme I toprovide a 4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline ofFormula XXXXV which is a subgenus of Formula IV.

[0146] In step (9) of Reaction Scheme VII, a4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline of Formula XXXXVis aminated using the method of step (8a) to provide a6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-4-amine of Formula XXXVIwhich is a subgenus of Formula II. The product or a pharmaceuticallyacceptable salt thereof can be isolated using conventional methods.

[0147] The invention also provides novel compounds useful asintermediates in the synthesis of compounds of Formula II. Theseintermediates have structural Formulas III and IV described in moredetail below.

[0148] One class of intermediate compounds has the Formula III:

[0149] wherein: X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-;

[0150] R₂ is selected from the group consisting of:

[0151] -hydrogen;

[0152] -alkyl;

[0153] -alkenyl;

[0154] -aryl;

[0155] -heteroaryl;

[0156] -heterocyclyl;

[0157] -alkyl-Y-alkyl;

[0158] -alkyl-Y-alkenyl;

[0159] -alkyl-Y-aryl; and

[0160] - alkyl or alkenyl substituted by one or more substituentsselected from the group consisting of:

[0161] —OH;

[0162] -halogen;

[0163] —N(R₃)₂;

[0164] —CO—N(R₃)₂;

[0165] —CO—C₁₋₁₀ alkyl;

[0166] —CO—O—C₁₋₁₀ alkyl;

[0167] —N₃;

[0168] -aryl;

[0169] -heteroaryl;

[0170] -heterocyclyl;

[0171] —CO-aryl; and

[0172] —CO-heteroaryl;

[0173] each R₃ is independently H or C₁₋₁₀ alkyl;

[0174] Y is —O—or —S(O)₀₋₂—;

[0175] n is 0 to 4; and

[0176] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl;

[0177] or a pharmaceutically acceptable salt thereof.

[0178] Another class of intermediates has the Formula IV:

[0179] wherein: X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-;

[0180] Z is —S—, —SO—, or —SO₂—;

[0181] R₁ is selected from the group consisting of:

[0182] -alkyl;

[0183] -aryl;

[0184] -heteroaryl;

[0185] -heterocyclyl;

[0186] -alkenyl;

[0187] —R₄-aryl;

[0188] —R₄-heteroaryl; and

[0189] —R₄-heterocyclyl;

[0190] R₂ is selected from the group consisting of:

[0191] -hydrogen;

[0192] -alkyl;

[0193] -alkenyl;

[0194] -aryl;

[0195] -heteroaryl;

[0196] -heterocyclyl;

[0197] -alkyl-Y-alkyl;

[0198] -alkyl-Y-alkenyl;

[0199] -alkyl-Y-aryl; and

[0200] -alkyl or alkenyl substituted by one or more substituentsselected from the group consisting of:

[0201] —OH;

[0202] -halogen;

[0203] —N(R₃)₂;

[0204] —CO-N(R₃)₂;

[0205] —CO—C₁₋₁₀ alkyl;

[0206] —CO—O—C₁₋₁₀ alkyl;

[0207] —N₃;

[0208] -aryl;

[0209] -heteroaryl;

[0210] -heterocyclyl;

[0211] —CO-aryl; and

[0212] —CO-heteroaryl;

[0213] each R₃ is independently H or C₁₋₁₀ alkyl;

[0214] R₄ is alkylene or alkenylene;

[0215] Y is —O— or —S(O)₀₋₂—;

[0216] n is 0 to 4; and

[0217] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl;

[0218] or a pharmaceutically acceptable salt thereof.

[0219] As used herein, the terms “alkyl”, “alkenyl” and the prefix“alk-” are inclusive of both straight chain and branched chain groupsand of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwisespecified, these groups contain from 1 to 20 carbon atoms, with alkenylgroups containing from 2 to 20 carbon atoms. Preferred groups have atotal of up to 10 carbon atoms. Cyclic groups can be monocyclic orpolycyclic and preferably have from 3 to 10 ring carbon atoms. Exemplarycyclic groups include cyclopropyl, cyclopropylmethyl, cyclopentyl,cyclohexyl and adamantyl.

[0220] In addition, the alkyl and alkenyl portions of -X- groups can beunsubstituted or substituted by one or more substituents, whichsubsuituents are selected from the groups consisting of alkyl, alkenyl,aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, andheterocyclylalkyl.

[0221] The term “haloalkyl” is inclusive of groups that are substitutedby one or more halogen atoms, including perfluorinated groups. This isalso true of groups that include the prefix “halo-”. Examples ofsuitable haloalkyl groups are chloromethyl, trifluoromethyl, and thelike.

[0222] The term “aryl” as used herein includes carbocyclic aromaticrings or ring systems. Examples of aryl groups include phenyl, naphthyl,biphenyl, fluorenyl and indenyl. The term “heteroaryl” includes aromaticrings or ring systems that contain at least one ring hetero atom (e.g.,O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl,quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl,tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl,benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl,quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl,purinyl, quinazolinyl, and so on.

[0223] “Heterocyclyl” includes non-aromatic rings or ring systems thatcontain at least one ring hetero atom (e.g., O, S, N) and includes allof the fully saturated and partially unsaturated derivatives of theabove mentioned heteroaryl groups. Exemplary heterocyclic groups includepyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl,piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl,isothiazolidinyl, and the like.

[0224] The aryl, heteroaryl, and heterocyclyl groups can beunsubstituted or substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkoxy, methylenedioxy,ethylenedioxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen,nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy,arylthio, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy,heteroarylthio, heteroarylalkoxy, heteroarylalkylthio, amino,alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl,alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl,alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl,alkanoyloxy, alkanoylthio, alkanoylamino, arylcarbonyloxy,arylcarbonylthio, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino,arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino,arylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino,heteroarylalkycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino,arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino,heteroarylalkylsulfonylamino, alkylaminocarbonylamino,alkenylaminocarbonylamino, arylaminocarbonylamino,arylalkylaminocarbonylamino, heteroarylaminocarbonylamino,heteroarylalkylcarbonylamino, and, in the case of heterocyclyl, oxo. Ifany other groups are identified as being “substituted” or “optionallysubstituted”, then those groups can also be substituted by one or moreof the above enumerated substituents.

[0225] Certain substituents are generally preferred. For example,preferred X groups include ethylene and n-butylene and preferred R₁groups are alkyl and aryl, with phenyl or substituted phenyl a preferredaryl group. Preferably no R substituents are present (i.e., n is 0).Preferred R₂ groups include hydrogen, alkyl groups having 1 to 4 carbonatoms (i.e., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,isobutyl, and cyclopropylmethyl), methoxyethyl, and ethoxymethyl. One ormore of these preferred substituents, if present, can be present in thecompounds of the invention in any combination.

[0226] The invention is inclusive of the compounds described herein inany of their pharmaceutically acceptable forms, including isomers (e.g.,diastereomers and enantiomers), salts, solvates, polymorphs, and thelike. In particular, if a compound is optically active, the inventionspecifically includes each of the compound's enantiomers as well asracemic mixtures of the enantiomers.

Pharmaceutical Compositions and Biological Activity

[0227] Pharmaceutical compositions of the invention contain atherapeutically effective amount of a compound of the invention asdescribed above in combination with a pharmaceutically acceptablecarrier.

[0228] The term “a therapeutically effective amount” means an amount ofthe compound sufficient to induce a therapeutic effect, such as cytokineinduction, antitumor activity, and/or antiviral activity. Although theexact amount of active compound used in a pharmaceutical composition ofthe invention will vary according to factors known to those of skill inthe art, such as the physical and chemical nature of the compound, thenature of the carrier, and the intended dosing regimen, it isanticipated that the compositions of the invention will containsufficient active ingredient to provide a dose of about 100 ng/kg toabout 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg, of thecompound to the subject. Any of the conventional dosage forms may beused, such as tablets, lozenges, parenteral formulations, syrups,creams, ointments, aerosol formulations, transdermal patches,transmucosal patches and the like.

[0229] The compounds of the invention can be administered as the singletherapeutic agent in the treatment regimen, or the compounds of theinvention may be administered in combination with one another or withother active agents, including additional immune response modifiers,antivirals, antibiotics, etc.

[0230] The compounds of the invention have been shown to induce theproduction of certain cytokines in experiments performed according tothe tests set forth below. These results indicate that the compounds areuseful as immune response modifiers that can modulate the immuneresponse in a number of different ways, rendering them useful in thetreatment of a variety of disorders.

[0231] Cytokines whose production may be induced by the administrationof compounds according to the invention generally include interferon-α(IFN-α) and/or tumor necrosis factor-α (TNF-α) as well as certaininterleukins (IL). Cytokines whose biosynthesis may be induced bycompounds of the invention include IFN-α, TNF-α, IL-1, IL-6, IL-10 andIL-12, and a variety of other cytokines. Among other effects, these andother cytokines can inhibit virus production and tumor cell growth,making the compounds useful in the treatment of viral diseases andtumors. Accordingly, the invention provides a method of inducingcytokine biosynthesis in an animal comprising administering an effectiveamount of a compound or composition of the invention to the animal.

[0232] Certain compounds of the invention have been found topreferentially induce the expression of IFN-α in a population ofhematopoietic cells such as PBMCs (peripheral blood mononuclear cells)containing pDC2 cells (precursor dendritic cell-type 2) withoutconcomitant production of significant levels of inflammatory cytokines.

[0233] In addition to the ability to induce the production of cytokines,the compounds of the invention affect other aspects of the innate immuneresponse. For example, natural killer cell activity may be stimulated,an effect that may be due to cytokine induction. The compounds may alsoactivate macrophages, which in turn stimulates secretion of nitric oxideand the production of additional cytokines. Further, the compounds maycause proliferation and differentiation of B-lymphocytes.

[0234] Compounds of the invention also have an effect on the acquiredimmune response. For example, although there is not believed to be anydirect effect on T cells or direct induction of T cell cytokines, theproduction of the T helper type 1 (Th1) cytokine IFN-γ is inducedindirectly and the production of the T helper type 2 (Th2) cytokinesIL-4, IL-5 and IL-13 are inhibited upon administration of the compounds.This activity means that the compounds are useful in the treatment ofdiseases where upregulation of the Th1 response and/or downregulation ofthe Th2 response is desired. In view of the ability of compounds of theinvention to inhibit the Th2 immune response, the compounds are expectedto be useful in the treatment of atopic diseases, e.g., atopicdermatitis, asthma, allergy, allergic rhinitis; systemic lupuserythematosis; as a vaccine adjuvant for cell mediated immunity; andpossibly as a treatment for recurrent fungal diseases and chlamydia.

[0235] The immune response modifying effects of the compounds make themuseful in the treatment of a wide variety of conditions. Because oftheir ability to induce the production of cytokines such as IFN-α and/orTNF-α, the compounds are particularly useful in the treatment of viraldiseases and tumors. This immunomodulating activity suggests thatcompounds of the invention are useful in treating diseases such as, butnot limited to, viral diseases including genital warts; common warts;plantar warts; Hepatitis B; Hepatitis C; Herpes Simplex Virus Type I andType II; molluscum contagiosum; variola, particularly variola major;HIV; CMV; VZV; rhinovirus; adenovirus; influenza; and para-influenza;intraepithelial neoplasias such as cervical intraepithelial neoplasia;human papillomavirus (HPV) and associated neoplasias; fungal diseases,e.g. candida, aspergillus, and cryptococcal meningitis; neoplasticdiseases, e.g., basal cell carcinoma, hairy cell leukemia, Kaposi'ssarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenousleukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneousT-cell lymphoma, and other cancers; parasitic diseases, e.g.pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis,trypanosome infection, and leishmaniasis; and bacterial infections,e.g., tuberculosis, and mycobacterium avium. Additional diseases orconditions that can be treated using the compounds of the inventioninclude actinic keratosis; eczema; eosinophilia; essentialthrombocythaemia; leprosy; multiple sclerosis; Ommen's syndrome; discoidlupus; Bowen's disease; Bowenoid papulosis; alopecia areata; theinhibition of Keloid formation after surgery and other types ofpost-surgical scars. In addition, these compounds could enhance orstimulate the healing of wounds, including chronic wounds. The compoundsmay be useful for treating the opportunistic infections and tumors thatoccur after suppression of cell mediated immunity in, for example,transplant patients, cancer patients and HIV patients.

[0236] An amount of a compound effective to induce cytokine biosynthesisis an amount sufficient to cause one or more cell types, such asmonocytes, macrophages, dendritic cells and B-cells to produce an amountof one or more cytokines such as, for example, IFN-α, TNF-α, IL-1, IL-6,IL-10 and IL-12 that is increased over the background level of suchcytokines. The precise amount will vary according to factors known inthe art but is expected to be a dose of about 100 ng/kg to about 50mg/kg, preferably about 10 μg/kg to about 5 mg/kg. The invention alsoprovides a method of treating a viral infection in an animal and amethod of treating a neoplastic disease in an animal comprisingadministering an effective amount of a compound or composition of theinvention to the animal. An amount effective to treat or inhibit a viralinfection is an amount that will cause a reduction in one or more of themanifestations of viral infection, such as viral lesions, viral load,rate of virus production, and mortality as compared to untreated controlanimals. The precise amount will vary according to factors known in theart but is expected to be a dose of about 100 ng/kg to about 50 mg/kg,preferably about 10 μg/kg to about 5 mg/kg. An amount of a compoundeffective to treat a neoplastic condition is an amount that will cause areduction in tumor size or in the number of tumor foci. Again, theprecise amount will vary according to factors known in the art but isexpected to be a dose of about 100 ng/kg to about 50 mg/kg, preferablyabout 10 μg/kg to about 5 mg/kg.

[0237] The invention is further described by the following examples,which are provided for illustration only and are not intended to belimiting in any way.

EXAMPLE 12-butyl-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0238]

Part A

[0239] A round bottom flask was charged with a magnetic stir bar,4-chloro-3-nitroquinoline (109.70 g, 525.87 mmol) and dichloromethane(500 mL). To the solution was added triethylamine (79.82 g, 788.81 mmol)and 4-amino-1-butanol (46.87 g, 525.87 mmol) to give a homogeneous, darkyellow solution. The reaction was judged to be complete after heating atreflux for 30 minutes. The solution was cooled and then partitionedbetween chloroform and saturated aqueous ammonium chloride. The layerswere separated and the aqueous layer was extracted with chloroform (1×).The organic layers were combined and then concentrated under reducedpressure to afford 4-[(3-nitroquinolin-4-yl)amino]butan-1-ol (104.67 g,400.60 mmol) as a dark yellow solid. This material was used withoutfurther purification.

Part B

[0240] A round bottom flask was charged with a magnetic stir bar,4-[(3-nitroquinolin-4-yl)amino]butan-1-ol (5.0 g, 19.14 mmol),triethylamine (2.91 g, 28.71 mmol), tert-butyldimethylsilyl chloride(3.75 g, 24.9 mmol), 4-dimethylaminopyridine (0.10 g) and chloroform (40mL) to give a dark yellow solution. The reaction was judged was tocomplete after stirring at ambient temperature for 2 hours. The solutionwas partitioned between ethyl acetate and saturated aqueous ammoniumchloride. The layers were separated and the organic layer was washedwith saturated aqueous sodium bicarbonate, dried over anhydrous sodiumsulfate, filtered and then concentrated under reduced pressure to affordN-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-3-nitroquinolin-4-amine(6.05 g, 16.11 mmol) as a yellow-green solid. This material was usedwithout further purification. MS (CI) for C₁₉H₂₉N₃O₃Si m/z 376 (MH⁺),342, 210.

Part C

[0241] A Parr vessel was charged withN-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-3-nitroquinolin-4-amine(6.05 g, 16.11 mmol), 5% platinum on carbon (3.0 g), and toluene (32mL). The vessel was placed on a Parr shaker and pressurized to 50 psi(3.5 Kg/cm²) hydrogen. After shaking for one hour, more catalyst (3.0 g)and toluene (15 mL) were added and the vessel was pressurized to 50 psi(3.5 Kg/cm²) hydrogen and shaking continued. The reaction was judged tobe complete after one hour. The catalyst was removed by filtrationthrough fluted paper. The filter cake was washed with toluene (50 mL)and the filtrates were combined. The volatiles were removed underreduced pressure to affordN-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)quinoline-3,4-diamine (5.57g, 16.11 mmol) as a dark oil. The material was used without furtherpurification.

Part D

[0242] A round bottom flask was charged with a magnetic stir bar,N-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)quinoline-3,4-diamine (5.57g, 16.11 mmol), trimethyl orthovalerate (5.23 g, 32.22 mmol) and toluene(47 mL). The reaction was heated to maintain a reflux that brought abouta slow distillation to facilitate removal of the methanol byproduct. Thereaction was judged to be complete after 15 hours at reflux. Thereaction was cooled and the volatiles were removed under reducedpressure to afford of2-butyl-1-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-1H-imidazo[4,5-c]quinoline(4.65 g, 11.30 mmol) as a thick, dark brown oil. The material was usedwithout further purification. MS (CI) for C₂₄H₃₇N₃OSi m/z 412 (MH⁺),298.

Part E

[0243] A round bottom flask was charged with a magnetic stir bar,2-butyl-1-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-1H-imidazo[4,5-c]quinoline(4.65 g, 11.30 mmol) and chloroform (57 mL). Solid 3-chloroperbenzoicacid (2.78 g, 12.43 mmol) was added portion wise to the solution over 15minutes and the reaction was stirred at ambient temperature for 1 hour.More 3-chloroperbenzoic acid (0.5 g, 2.9 mmol) was added and after 30minutes the starting material was completely consumed. The solution waspartitioned between chloroform and aqueous saturated sodium bicarbonate.The layers were separated. The organic layer was washed with saturatedaqueous sodium bicarbonate and brine, dried over anhydrous sodiumsulfate, filtered and then concentrated under reduced pressure to afford2-butyl-1-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-1H-imidazo[4,5-c]quinoline-5N-oxide(4.83 g, 11.30 mmol) as a dark oil. The material was used withoutfurther purification.

Part F

[0244] A round bottom flask was charged with a magnetic stir bar,2-butyl-1-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-1H-imidazo[4,5-c]quinoline-5N-oxide(11.30 mmol) and anhydrous dimethyl formamide (57 mL) under a nitrogenatmosphere. Phosphorus oxychloride (1.91 g, 12.43 mmol) was added to thereaction mixture in a drop wise fashion to give a homogeneous solutionafter complete addition. The reaction was judged to be complete afterstirring for 1.5 hours at ambient temperature and was then partitionedbetween dichloromethane and saturated aqueous sodium bicarbonate. Thelayers were separated and the organic portion was washed with aqueoussaturated sodium bicarbonate and brine, dried over anhydrous sodiumsulfate, filtered and then concentrated under reduced pressure to afford2-butyl-4-chloro-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinoline (3.65 g,10.42 mmol) as a dark brown solid. The material was used without furtherpurification. MS (CI) for C₁₈H₂₁C₁₂N₃ m/z 350 (MH⁺), 314.

Part G

[0245] A round bottom flask was charged with a magnetic stir bar,2-butyl-4-chloro-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinoline (1.18 g,3.37 mmol), benzenethiol (0.56 g, 5.05 mmol), triethylamine (0.68 g,6.74 mmol), and dimethyl formamide (15 mL) under a nitrogen atmosphere.The reaction mixture was heated to 80° C. to give a homogeneous solutionthat was maintained at 80° C. for 2.5 hours. HPLC analysis indicated nostarting material and a 3:1 mixture of2-butyl-4-chloro-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinoline and2-butyl-4-(phenylthio)-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinoline.The solution was cooled and then partitioned between ethyl acetate andaqueous saturated sodium bicarbonate. The layers were separated and theorganic layer was washed with aqueous saturated sodium bicarbonate andbrine, dried over anhydrous sodium sulfate, filtered and thenconcentrated under reduced pressure to afford a 3:1 mixture of theproducts named above (1.43 g). The material was used without furtherpurification.

Part H

[0246] A 3:1 mixture of2-butyl-4-chloro-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinoline to2-butyl-4-(phenylthio)-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinoline(1.38 g) and a solution of 7% ammonia in methanol (30 mL) were combinedin a bomb and heated to 150° C. The reaction was judged to be completeafter 5 hours. The volatiles were removed under reduced pressure and theresulting residue was stirred in water and made basic (pH 10) with solidsodium carbonate. The aqueous mixture was extracted with chloroform(3×). The combined organic layers were washed with saturated aqueoussodium bicarbonate and brine, dried over anhydrous sodium sulfate,filtered and then concentrated under reduced pressure to afford a yellowcrystalline solid. The solid (0.8 g) was dissolved in ethyl acetate (50mL) and brought to reflux. Activated charcoal (0.4 g) was added; theresulting mixture was heated at reflux for 5 minutes and then thecharcoal was removed by filtration through fluted paper to provide acolorless solution. The solution was concentrated under reduced pressureto give a solid that was recrystallized from ethyl acetate and hexanesto provide2-butyl-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.51g, 1.25 mmol) as white needles, m.p. 118-120° C.

[0247] Analysis. Calculated for C₂₄H₂₈N₄S: % C 71.25; % H, 6.98; % N,13.85. Found % C 71.12; % H, 6.81; % N, 13.62. ¹H-NMR (300 MHz, DMSO) δ8.02 (d, J=8.3 Hz, 1H), δ 7.61 (d, J=8.3 Hz, 1H), δ 7.41 (t, J=8.3 Hz,1H), δ 7.16-7.30 (m, 6H), δ 6.46 (bs, 2H), 8 4.52 (t, J=7.6 Hz, 2H),δ3.02 (t, J=7.3 Hz, 2H), δ 2.89 (t, J=7.8 Hz, 2H), δ 1.95 (m, 2H), δ1.75 (m, 4H), δ 1.43 (sextet, J=7.3 Hz, 2H), δ 0.94 (t, J=7.3 Hz, 3H) MS(CI) for C₂₄H₂₈N₄S m/z 405 (MH⁺), 282, 241.

EXAMPLE 22-butyl-1-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride

[0248]

Part A

[0249] A round bottom flask was charged with a magnetic stir bar,2-(4-amino-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)ethanol(1.0 g, 3.47 mmol), tert-butyldimethylsilyl chloride (1.62 g, 10.75mmol), triethylamine (1.58 g, 15.62 mmol), 4-dimethylaminopyridine (0.1g), and chloroform (30 mL) to give a heterogeneous reaction mixture. Thereaction was judged to be complete after stirring at 60° C. for 2 hours.The solution was partitioned between ethyl acetate and saturated aqueousammonium chloride. The layers were separated and the organic layer waswashed with aqueous saturated sodium bicarbonate and brine, dried overanhydrous sodium sulfate, filtered and then concentrated under reducedpressure to afford a 3:1 mixture of2-butyl-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amineand2-butyl-N-[tert-butyl(dimethyl)silyl]-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine(1.79 g) as a dark brown oil. The material was used without furtherpurification.

Part B

[0250] A round bottom flask was charged with a magnetic stir bar, a 3:1mixture of2-butyl-1-(2-{[tert-butyl(dimethyl)silyl]oxy)ethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amineand2-butyl-N-[tert-butyl(dimethyl)silyl]-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine(1.6 g) and a 1 M solution of acetic acid in dichloromethane (85 mL) toprovide a homogenous solution. The reaction was judged to be completeafter stirring at ambient temperature for 30 minutes. The solution waspartitioned between chloroform and brine. The layers were separated andthe organic layer was washed with aqueous saturated sodium bicarbonateand brine, dried over anhydrous sodium sulfate, filtered and thenconcentrated under reduced pressure to afford a dark brown oil. Thematerial was purified by chromatography over silica gel (95/4/1dichloromethane/methanol/ammonium hydroxide [14.8 M in water]) toprovide2-butyl-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine(1.24 g, 3.10 mmol) as a colorless oil.

Part C

[0251] A round bottom flask was charged with a magnetic stir bar,2-butyl-l-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine(0.83 g, 2.06 mmol), di-tert-butyl dicarbonate (1.79 g; 8.24 mmol),triethylamine (0.52 g, 5.15 mmol), 4-dimethylaminopyridine (0.1 g), andanhydrous tetrahydrofuran (21 mL) under a nitrogen atmosphere. Thereaction mixture was heated to 60° C. to give a homogeneous solutionthat was maintained at 60° C. for 2.5 hours at which time the reactionwas judged to be complete. The solution was cooled to ambienttemperature and a 1 M solution of tetrabutylammonium fluoride intetrahydrofuran (2.27 mL, 2.27 mmol) was added. The reaction was judgedto be complete after stirring at ambient temperature for 30 minutes. Thesolution was partitioned between ethyl acetate and saturated aqueousammonium chloride. The layers were separated. The organic layer waswashed with saturated aqueous sodium bicarbonate and brine, dried overanhydrous sodium sulfate, filtered and then concentrated under reducedpressure to afford a light yellow solid. The material was purified bychromatography over silica gel (95/5 dichloromethane/methanol) toprovide di(tert-butyl)2-butyl-1-(2-hydroxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-ylimidodicarbonate(0.55 g, 1.13 mmol) as a clear gum.

Part D

[0252] A round bottom flask was charged with a magnetic stir bar,di(tert-butyl)2-butyl-1-(2-hydroxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-ylimidodicarbonate(0.55 g, 1.13 mmol) and anhydrous dichloromethane (11 mL) under anitrogen atmosphere. The resulting homogeneous solution was cooled to−10° C. in a methanol/ice bath. To the cooled solution was addedtriethylamine (0.23 g, 2.26 mmol) and methanesulfonyl chloride (0.19 g,1.70 mmol). The reaction was judged to be complete after stirring at−10° C. for 15 minutes and was then partitioned between ethyl acetateand saturated aqueous ammonium chloride. The layers were separated. Theorganic layer was washed with saturated aqueous sodium bicarbonate andbrine, dried over anhydrous sodium sulfate, filtered and thenconcentrated under reduced pressure to afford2-{4-[bis(tert-butoxycarbonyl)amino]-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl}ethylmethanesulfonate (0.61 g, 1.08 mmol) as a gummy yellow solid. Thematerial was used without further purification. MS (CI) for C₂₇H₄₂N₄O₇Sm/z 567 (MH⁺), 467, 367, 271.

Part E

[0253] A round bottom flask was charged with a magnetic stir bar,2-{4-[bis(tert-butoxycarbonyl)amino]-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl}ethyl methanesulfonate (0.61 g, 1.08 mmol), benzenethiol (0.21 g, 1.88mmol), triethylamine (0.25 g, 2.43 mmol) and anhydrous dimethylformamide (11 mL) under a nitrogen atmosphere. The reaction mixture washeated to 80° C. to give a dark yellow, homogeneous solution that wasmaintained at 80° C. for 2.5 hours at which time the reaction was judgedto be complete. The solution was cooled and then partitioned betweenethyl acetate and saturated aqueous sodium bicarbonate. The layers wereseparated. The organic layer was washed with saturated aqueous sodiumbicarbonate and brine, dried over anhydrous sodium sulfate, filtered andthen concentrated under reduced pressure to afford a yellow oil. Thematerial was purified by chromatography over silica gel (95/5dichloromethane/methanol) to provide di(tert-butyl)2-butyl-1-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-ylimidodicarbonate(0.54 g, 0.93 mmol) as a light yellow oil. MS (CI) for C₃₂H₄₄N₄O₄S m/z581 (MH⁺), 481, 381, 245.

Part F

[0254] A round bottom flask was charged with a magnetic stir bar,di(tert-butyl)2-butyl-1-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-ylimidodicarbonate(0.50 g, 0.86 mmol), a 4 M solution of hydrochloric acid in dioxane (5mL), and dichloromethane (5 mL). The reaction was judged to be completeafter stirring at ambient temperature for 2 hours. The volatiles wereremoved under reduced pressure to afford an off white solid. Thematerial was recrystallized from acetonitrile to provide2-butyl-1-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride (0.17 g, 1.30 mmol) as fluffy white needles, m.p. 237-238°C. Analysis. Calculated for C₂₂H₂₈N₄S .(H₂O)_(1/4).(HCl)₂: % C 57.70; %H, 6.71; % N, 12.23. Found % C 57.62; % H, 6.57; % N, 12.41.

[0255]¹H-NMR (300 MHz, DMSO) δ 7.81 (bs, 2H), δ 7.22-7.39 (m, 5H), δ4.64 (t, J=6.8 Hz, 2H), δ 3.40 (t, J=6.8 Hz, 2H), δ 2.75 (m, 6H), δ 1.71(m, 6H), δ 1.34 (sextet, J=7.3 Hz, 2H), δ 0.89 (t, J=7.3 Hz, 3H). MS(CI) for C₂₂H₂₈N₄S (H₂O)_(1/4) (HCl)₂ m/z 381 (MH⁺), 245, 137.

EXAMPLE 32-butyl-1-[4-(phenylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0256]

Part A

[0257] Using the general method of Example 1 Part E,2-butyl-1-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-1H-imidazo[4,5-c]quinoline(16.0 g, 38.87 mmol) was oxidized to2-butyl-1-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-1H-imidazo[4,5-c]quinoline-5N-oxide(16.61 g, 38.87 mmol) which was isolated without purification as a tansolid.

Part B

[0258] A round bottom flask was charged with a magnetic stir bar,2-butyl-1-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-1H-imidazo[4,5-c]quinoline-5N-oxide(16.61 g, 38.87 mmol), a 14.8 M solution of ammonium hydroxide in water(75 mL) and chloroform (200 mL). To the rapidly stirring solution wasadded p-toluenesulfonyl chloride (8.15 g, 42.76 mmol) in a portion wisefashion resulting in a mild exotherm. The reaction was judged to becomplete after stirring at ambient temperature for 10 minutes. Thesolution was partitioned between chloroform and aqueous saturated sodiumbicarbonate. The layers were separated. The organic layer was washedwith saturated aqueous sodium bicarbonate and brine, dried overanhydrous sodium sulfate, filtered and then concentrated under reducedpressure to afford an off-white solid. The material was triturated withethyl ether and collected by filtration to provide2-butyl-1-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-1H-imidazo[4,5-c]quinolin-4-amine(9.3 g, 21.80 mmol) as a fine white powder. The material was usedwithout further purification.

Part C

[0259] A round bottom flask was charged with a magnetic stir bar,2-butyl-1-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-1H-imidazo[4,5-c]quinolin-4-amine(9.2 g, 21.56 mmol), a 1M solution of tetrabutylammonium fluoride intetrahydrofuran (23.72 mL, 23.72 mmol), and anhydrous tetrahydrofuran(100 mL) to give a homogeneous, light orange solution. The reaction wasjudged to be complete after stirring at ambient temperature for 1 hour.While stirring, water (100 mL) was added and resulted in a mildexotherm. The volatiles were removed under reduced pressure until asolid precipitated out of solution. The solid was collected byfiltration and washed with water (20 mL) and acetone (20 mL) to afford awhite solid. The material was triturated with ethyl ether (50 mL) andcollected by filtration to provide4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (6.12 g,19.59 mmol) as a fine white solid, m.p. 184-186° C.

[0260] Analysis. Calculated for C₁₈H₂₄N₄O: % C 69.20; % H, 7.74; % N,17.93. Found % C 69.05; % H, 8.02; % N, 18.03. MS (CI) for C₁₈H₂₄N₄O m/z313 (MH⁺).

Part D

[0261] A round bottom flask was charged with a magnetic stir bar,4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (7.3 g,23.37 mmol), triethylamine (3.55 g, 35.06 mmol), and anhydrous dimethylformamide (93 mL) under a nitrogen atmosphere. To the stirred solutionwas added phosphorus oxychloride (3.94 g, 25.70 mmol) in a drop wisefashion resulting in an exotherm to give a dark yellow heterogeneousreaction mixture. The reaction mixture was heated to 60° C. to give ahomogeneous solution that was maintained at 60° C. for 5 hours at whichtime the starting material was completely consumed. The volatiles wereremoved under reduced pressure to give a dark brown oil. The materialwas partitioned between chloroform and saturated aqueous sodiumbicarbonate. The layers were separated and the aqueous layer wasextracted with chloroform (1×). The organic layers were combined and thevolatiles removed under reduced pressure to afford a 2:1 mixture ofN′-[2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-yl]-N,N-dimethylimidoformamideand 2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (7.70 g)as an off-white solid. The material was used without furtherpurification.

Part E

[0262] A round bottom flask was charged with a magnetic stir bar, a 2:1mixture ofN′-[2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-yl]-N,N-dimethylimidoformamideand 2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.3 g),benzenesulfinic acid sodium salt (1.67 g, 10.11 mmol), and anhydrousdimethyl formamide (15 mL) under a nitrogen atmosphere. The resultingsolution was heated to 100° C. to give a homogeneous solution that wasmaintained at 100° C. for 90 hours at which time the starting materialswere completely consumed. The solution was cooled and then partitionedbetween chloroform and water. The layers were separated. The organiclayer was washed with saturated aqueous sodium bicarbonate and brine,dried over anhydrous sodium sulfate, filtered and then concentratedunder reduced pressure to afford a dark yellow gum. The material wasdissolved in methanol (20 mL) and a 4 M solution of hydrochloric acid indioxane (3.02 mL, 12.1 mmol). The light orange solution was stirred atambient temperature for 12 hours at which time the reaction was judgedto be complete. The volatiles were removed under reduced pressure togive a light yellow gum. The material was partitioned between chloroformand saturated aqueous sodium bicarbonate. The layers were separated andthe aqueous layer was extracted with chloroform (1×). The organic layerswere combined, washed with brine, dried over anhydrous sodium sulfate,filtered and then concentrated under reduced pressure to afford a lightyellow solid. The material was purified by chromatography over silicagel (95/5 dichloromethane/methanol) to give an off-white solid. Thesolid (0.63 g) was dissolved in ethyl acetate (50 mL) and brought toreflux. Activated charcoal (0.6 g) was added and the resulting mixturewas heated at reflux for 5 minutes. The charcoal was removed byfiltration through fluted paper to provide a colorless solution. Thesolution was concentrated under reduced pressure to give a solid thatwas recrystallized from ethyl acetate and hexanes to provide2-butyl-1-[4-(phenylsulfonyl)butyl]-H-imidazo[4,5-c]quinolin-4-amine(0.37 g, 0.85 mmol) as a white fluffy solid, m.p. 179-180° C. Analysis.Calculated for C₂₄H₂₈N₄O₂S: % C 66.03; % H, 6.46; % N, 12.83. Found % C65.88; % H, 6.49; % N, 12.76.

[0263]¹H-NMR (300 MHz, DMSO) δ 7.98 (d, J=8.3 Hz, 1H), δ 7.82 (m, 2H) δ7.73 (d, J=7.3 Hz, 1H), δ 7.62 (m, 3H) δ 7.41 (t, J=7.6 Hz, 1H), δ 7.22(t, J=7.6 Hz, 1H), δ 6.45 (bs, 2H), δ 4.51 (t, J=7.3 Hz, 2H), δ 3.90 (t,J=7.8 Hz, 2H), δ 2.86 (t, J=7.6 Hz, 3H), δ 1.69-1.90 (m, 6H), δ 1.43(sextet, J=7.3 Hz, 2H), δ 0.95 (t, J=7.3 Hz, 3H) MS (CI) for C₂₄H₂₈N₄O₂Sm/z 437 (MH⁺), 295.

EXAMPLE 42-butyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0264]

Part A

[0265] A round bottom flask was charged with a magnetic stir bar, a 2:1mixture ofN′-[2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-yl]-N,N-dimethylimidoformamideand 2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (6.17g), a 4 M solution of hydrochloric acid in dioxane (21.15 mL, 84.56mmol), and methanol (200 mL) to provide a light orange solution. Thereaction was judged to be complete after stirring at ambient temperaturefor 43 hours. The volatiles were removed under reduced pressure and theresulting light yellow solid was partitioned between chloroform andsaturated aqueous sodium bicarbonate. The layers were separated and theaqueous layer was extracted with chloroform (1×). The organic layerswere combined, dried over anhydrous sodium sulfate, filtered and thenconcentrated under reduced pressure to afford2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (4.65 g,14.05 mmol) as an off-white solid. The material was used without furtherpurification. MS (CI) for C₁₈H₂₃ClN₄ m/z 331 (MH⁺), 295.

Part B

[0266] A round bottom flask was charged with a magnetic stir bar,2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 4.53mmol), sodium thiomethoxide (0.48 g, 6.80 mmol), and anhydrous dimethylformamide (18 mL) under a nitrogen atmosphere. The reaction mixture washeated to 60° C. to give a homogeneous solution that was maintained at60° C. for 16 hours at which time the starting material was completelyconsumed. The solution was cooled and then partitioned betweenchloroform and water. The layers were separated and the organic layerwas washed with saturated aqueous sodium bicarbonate. The combinedaqueous layers were extracted with chloroform (1×). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and then concentrated under reduced pressure to afford a darkbrown oil. The material was purified by chromatography over silica gel(90/10 dichloromethane/methanol) to provide a light yellow solid. Thesolid was recrystallized from dimethyl formamide and water to give2-butyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.83g, 2.42 mmol) as light yellow needles, m.p. 127-130° C.

[0267] Analysis. Calculated for C₁₉H₂₆N₄S: % C 66.63; % H, 7.65; % N,16.36. Found % C 66.68; % H, 7.53; % N, 16.35 ¹H-NMR (500 MHz, DMSO) δ8.04 (d, J=8.3 Hz, 1H), δ 7.61 (d, J=8.3 Hz, 1H), δ 7.41 (t, J=8.3 Hz,1H), δ 7.25 (t, J=8.3 Hz, 1H), δ 6.43 (bs, 2H), δ 4.52 (t, J=7.6 Hz,2H), δ 2.92 (t, J=7.8 Hz, 2H), δ 2.53 (t, J=7.3 Hz, 2H), δ 2.01 (s, 3H),δ 1.90 (m, 2H) δ 1.80 (p, J=7.8 Hz, 2H) δ 1.71 (p, J=7.3 Hz, 2H) δ 1.46(sextet, J=7.3 Hz, 2H), δ 0.96 (t, J=7.3 Hz, 3H) MS (CI) for C₁₉H₂₆N₄Sm/z 343 (MH⁺), 295, 241.

EXAMPLE 52-butyl-1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0268]

Part A

[0269] A round bottom flask was charged with a magnetic stir bar,2-butyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.2g, 3.50 mmol), and chloroform (18 mL). Solid 3-chloroperbenzoic acid(1.72 g, 7.71 mmol) was added to the resulting solution portion wiseover 15 minutes. The reaction was judged to be complete after stirringat ambient temperature for 5 minutes. The solution was partitionedbetween chloroform and 1% aqueous sodium carbonate. The layers wereseparated and the organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and then concentrated under reducedpressure to afford a light brown solid. The material was purified bychromatography over silica gel (90/10 dichloromethane/methanol) toprovide an off-white solid. The solid was recrystallized fromacetonitrile and water to give2-butyl-1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine(0.61 g, 1.63 mmol) as off-white needles, m.p. 164-165° C.

[0270] Analysis. Calculated for C₁₉H₂₆N₄O₂S: % C 60.94; % H, 7.00; % N,14.96. Found % C 60.71; % H, 6.94; % N, 14.94. ¹H-NMR (300 MHz, DMSO) δ8.03 (d, J=8.3 Hz, 1H), δ 7.61 (d, J=8.3 Hz, 1H), δ 7.42 (t, J=8.3 Hz,1H), δ 7.26 (t, J=8.3 Hz, 1H), δ 6.46 (bs, 2H), δ 4.56 (t, J=7.6 Hz,2H), δ 3.21 (t, J=7.3 Hz, 2H), δ 2.96 (s, 3H), δ 2.93 (t, J=7.8Hz, 2H),δ 1.91 (m, 4H), δ 1.81 (p, J=7.3 Hz, 2H), δ 1.45 (sextet, J=7.3 Hz, 2H),δ 0.96 (t, J=7.3 Hz, 3H) MS (CI) for C₁₉H₂₆N₄O₂S m/z 375 (MH⁺), 295

EXAMPLE 6 1-[2-(phenylthio)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0271]

Part A

[0272] A round bottom flask was charged with a magnetic stir bar,2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (8.46 g, 37.06 mmol),and thionyl chloride (68.99 g, 57.99 mmol) under a nitrogen atmosphere.The reaction mixture was heated to 80° C. to give a heterogeneousreaction mixture that was maintained at 80° C. for 2 hours at which timethe starting material was completely consumed. The solution was cooledand quenched by the addition of water (400 mL). To the stirred solutionwas added solid sodium carbonate until the pH reached 10 at which time asolid precipitated out of solution. The solid was collected byfiltration to afford 1-(2-chloroethyl)-1H-imidazo[4,5-c]quinolin-4-amine(7.86 g, 31.86 mmol) as an off-white solid. The material was usedwithout further purification.

Part B

[0273] A round bottom flask was charged with a magnetic stir bar,1-(2-chloroethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 8.11 mmol),sodium benzenethiolate (1.79 g, 12.16 mmol), and anhydrous dimethylsulfoxide (40 mL) under a nitrogen atmosphere. The reaction mixture washeated to 100° C. to give a homogeneous solution that was maintained at100° C. for 30 minutes at which time the starting material wascompletely consumed. The hot solution was poured into rapidly stirredwater (300 mL) which caused a solid to precipitate out of solution. Thesolid was collected by filtration to afford an off-white solid. Thematerial was triturated with acetonitrile and collected by filtration togive 1-[2-(phenylthio)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (2.08 g,6.49 mmol) as an off-white powder, m. p. 233-235° C.

[0274] Analysis. Calculated for C₁₈H₁₆N₄S: % C 67.47; % H, 5.03; % N,17.49. Found: % C 67.20; % H, 4.95; % N, 17.52 ¹H-NMR (300 MHz, DMSO) δ8.14 (s, 1H), δ 7.76 (d, J=8.3 Hz, 1H), δ 7.60 (t, J=8.3 Hz, 1H), δ7.28-7.44 (m, 6H), δ 7.12 (t, J=8.3 Hz, 1H), δ 6.58 (bs, 2H), δ 4.79 (t,J=6.8 Hz, 2H), δ 3.48 (t, J=6.8 Hz, 2H) MS (CI) for C₁₈H₁₆N₄S m/z 321(MH⁺), 185, 137

EXAMPLE 7 1-[4-(phenylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0275]

Part A

[0276] A round bottom flask was charged with a magnetic stir bar,N,N-dibenzyl-1H-imidazo[4,5-c]quinolin-4-amine (20.0 g, 55.04 mmol),sodium hydride (3.3 g, 60% dispersion, 82.56 mmol), and anhydrousdimethyl formamide (275 mL) under a nitrogen atmosphere. After thereaction mixture had stirred at ambient temperature for 2 hours,4-chloro-1-iodobutane (19.23 g, 88.06 mmol) was added and the resultinghomogeneous solution was stirred at ambient temperature for 48 hours atwhich time the starting material was consumed. The solution waspartitioned between ethyl acetate and water. The layers were separatedand the organic layer was washed with saturated aqueous sodiumbicarbonate and brine, dried over anhydrous sodium sulfate, filtered andthen concentrated under reduced pressure to afford a light yellow solid.The material was recrystallized from ethyl acetate and hexanes to giveN,N-dibenzyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (20.7g, 45.49 mmol) as white needles. MS (CI) for C₂₈H₂₇CIN₄ m/z 455 (MH⁺),365, 329, 239.

Part B

[0277] A round bottom flask was charged with a magnetic stir bar,N,N-dibenzyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (7.0 g,15.38 mmol), sodium benzenethiolate (3.46 g, 26.15 mmol), and anhydrousdimethyl formamide (77 mL) under a nitrogen atmosphere. The reactionmixture was heated to 60° C. to give a heterogeneous mixture that wasmaintained at 60° C. for 4 hours at which time the starting material wascompletely consumed. The cooled solution was partitioned between ethylacetate and water. The layers were separated. The organic layer waswashed with saturated aqueous sodium bicarbonate and brine, dried overanhydrous sodium sulfate, filtered and then concentrated under reducedpressure to afford a colorless oil. The material was purified bychromatography over silica gel (80/20 hexanes/ethyl acetate) to provideN,N-dibenzyl-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine(7.5 g, 14.19 mmol) as a colorless oil. MS (CI) for C₃₄H₃₂N₄S m/z 529(MH⁺), 439, 349.

Part C

[0278] A round bottom flask was charged with a magnetic stir bar,N,N-dibenzyl-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine(3.64 g, 6.88 mmol) and chloroform (34 mL). Solid 3-chloroperbenzoicacid (3.39 g, 15.14 mmol) was added portion wise to the resultingsolution over 5 minutes. The reaction was judged to be complete afterstirring at ambient temperature for 5 minutes. The solution waspartitioned between chloroform and 1% aqueous sodium carbonate. Thelayers were separated. The organic layer was washed with brine, driedover anhydrous sodium sulfate, filtered and then concentrated underreduced pressure to afford a red gum. The material was purified bychromatography over silica gel (dichloromethane) to provideN,N-dibenzyl-1-[4-(phenylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine(2.85 g, 5.08 mmol) as a light pink gum. MS (CI) for C₃₄H₃₂N₄O₂S m/z 561(MH⁺), 471, 381.

Part D

[0279] A round bottom flask was charged with a magnetic stir bar,N,N-dibenzyl-1-[4-(phenylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine(1.0 g, 1.78 mmol), triflic acid (2.68 g, 17.83 mmol), and anhydrousdichloromethane (14 mL) under a nitrogen atmosphere. The reaction wasjudged to be complete after stirring at ambient temperature for 24hours. The solution was partitioned between chloroform and excessaqueous sodium hydroxide (20%). The layers were separated. The aqueouslayer was extracted with chloroform (3×). The organic layers werecombined and then concentrated under reduced pressure to afford a lightbrown solid. The material was purified by chromatography over silica gel(90/10 dichloromethane/methanol) to provide a fine white powder whichwas recrystallized from acetonitrile to give1-[4-(phenylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.32 g,0.84 mmol) as white needles, m. p. 175-177° C.

[0280] Analysis. Calculated for C₂₀H₂₀N₄O₂S: % C 63.14; % H, 5.30; % N,14.73. Found: % C 63.14; % H, 5.24; % N, 14.77 ¹H-NMR (300 MHz, DMSO) δ8.15 (s, 1H), δ 8.01 (d, J=8.3 Hz, 1H), δ 7.80 (m, 2H), δ 7.71 (m, 1H),δ 7.60 (m, 3H), δ 7.44 (t, J=8.3 Hz, 1H), δ 7.24 (t, J=8.3 Hz, 1H), δ6.59 (bs, 2H), δ 4.59 (t, J=6.8 Hz, 2H), δ 3.38 (t, J=7.8 Hz, 2H), δ1.93 (m, 2H), δ 1.58 (m, 2H) MS (CI) for C₂₀H₂₀N₄O₂S m/z 381 (MH⁺), 239.

EXAMPLE 8 1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0281]

Part A

[0282] Using the general method of Example 7 Part B,N,N-dibenzyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (5.0 g,10.99 mmol) was converted toN,N-dibenzyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amineusing sodium thiomethoxide (1.16 g, 16.48 mmol). The material waspurified by chromatography over silica gel (80/20 hexanes/ethyl acetate)to provide the product (4.91 g, 10.52 mmol) as a colorless oil. MS (CI)for C₂₉H₃₀N₄S m/z 467 (MH⁺), 377, 287, 185.

Part B

[0283] Using the general method of Example 7 Part C,N,N-dibenzyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine(4.91 g, 15.52 mmol) was oxidized toN,N-dibenzyl-1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-aminewhich was purified by chromatography over silica gel (80/20hexanes/ethyl acetate) to provide the product (4.53 g, 9.08 mmol) as alight orange solid. MS (CI) for C₂₉H₃₀N₄O₂S m/z 499 (MH⁺), 409, 319.

Part C

[0284] Using the general method of Example 7 Part D,N,N-dibenzyl-1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine(4.53 g, 9.08 mmol) was converted to1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine. Thematerial was recrystallized from methanol and water to afford the titlecompound (1.33 g, 4.18 mmol) as white needles, m.p. 203-204° C.

[0285] Analysis. Calculated for C₁₅H₁₈N₄O₂S: % C 56.58; % H, 5.70; % N,17.60. Found: % C 56.33; % H, 5.63; % N, 17.41 ¹H-NMR (300 MHz, DMSO) δ8.22 (s, 1H), δ 8.06 (d, J=8.3 Hz, 1H), δ 7.62 (d, J=8.3 Hz, 1H), δ 7.45(t, J=8.3 Hz, 1H), δ 7.27 (t, J=8.3 Hz, 1H), δ 6.59 (bs, 2H), δ 4.65 (t,J=6.8 Hz, 2H), δ 3.19 (t, J=7.8 Hz, 2H), δ 2.93 (s, 3H), δ 1.99 (m, 2H),δ 1.74 (m, 2H) MS (CI) for C₁₅H₁₈N₄O₂S m/z 319 (MH⁺), 239.

EXAMPLE 9 1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0286]

Part A

[0287] Using the general method of Example 1 Part D,N-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)quinoline-3,4-diamine (101.21g, 292.90 mmol) was cyclized to1-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-1H-imidazo[4,5-c]quinolineusing triethyl orthoformate (65.11 g, 439.35 mmol). The product (75.0 g,210.93 mmol) was isolated as a brown oil and used without furtherpurification.

Part B

[0288] Using the general method of Example 1 Part E,1-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-1H-imidazo[4,5-c]quinoline(42.2 g, 118.69 mmol) was oxidized to1-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-1H-imidazo[4,5-c]quinoline-5N-oxide(44.10 g, 118.69 mmol) which was isolated without further purificationas a tan solid.

Part C

[0289] Using the general method of Example 3 Part B,1-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-1H-imidazo[4,5-c]quinoline-5N-oxide(44.10 g, 118.69 mmol) was aminated to provide1-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-1H-imidazo[4,5-c]quinolin-4-amine.The material was triturated with ethyl ether and collected by filtrationto afford the product (21.54 g, 58.12 mmol) as a light brown solid whichwas used without further purification.

Part D

[0290] Using the general method of Example 3 Part C,1-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-1H-imidazo[4,5-c]quinolin-4-amine(21.5 g, 58.02 mmol) was converted to4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol. The material wastriturated with cold methanol (0° C.) and collected by filtration toafford the product (13.92 g, 54.30 mmol) which was used without furtherpurification. MS (CI) for C₁₄H₁₆N₄O m/z 257 (MH⁺), 185.

Part E

[0291] Using the general method of Example 6 Part A,4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (5.0 g, 19.51 mmol)was chlorinated to provide1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (4.92 g, 17.91 mmol)which was isolated without further purification as an off-white solid.

Part F

[0292] Using the general method of Example 6 Part B, except that thereaction temperature was lowered to 80° C.,1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.46 mmol)was converted to1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine. The resultingsolid (1.53 g) was dissolved in acetonitrile (90 mL) and brought toreflux. Activated charcoal (0.9 g) was added and the resulting mixturewas heated at reflux for 5 minutes and then the charcoal was removed byfiltration through fluted paper to provide a colorless solution. Thetitle compound (0.86 g, 2.47 mmol) was isolated as white needles, m.p158-160° C.

[0293] Analysis. Calculated for C₂₀H₂₀N₄S: % C 68.94; % H, 5.79; % N,16.08. Found: % C 68.70; % H, 5.74; % N, 16.08 ¹H-NMR (300 MHz, DMSO) δ8.18 (s, 1H), δ 8.05 (d, J=8.3 Hz, 1H), δ 7.63 (d, J=8.3 Hz, 1H), δ 7.45(t, J=8.3 Hz, 1H), δ 7.26 (m, 5H), δ 7.14-7.19 (m, 1H), δ 6.60 (bs, 2H),δ 4.62 (t, J=6.8 Hz, 2H), δ 3.00 (t, J=7.3 Hz, 2H), δ 2.00 (m, 2H), δ1.61 (m, 2H) MS (CI) for C₂₀H₂₀N₄S m/z 349 (MH⁺), 185.

EXAMPLE 10 1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0294]

Part A

[0295] Using the general method of Example 6 Part B, except that thereaction temperature was lowered to 80° C.,1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.46 mmol)was converted to1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine using sodiumthiomethoxide (0.88 g, 12.56 mmol) in lieu of sodium benzenethiolate.The resulting solid (1.26 g) was dissolved in acetonitrile (40 mL) andbrought to reflux. Activated charcoal (0.7 g) was added, the resultingmixture was heated at reflux for 5 minutes and then the charcoal wasremoved by filtration through fluted paper to provide a colorlesssolution. The solution was concentrated under reduced pressure to give asolid that was recrystallized from acetonitrile. The title compound(0.66 g, 2.30 mmol) was isolated as white needles, m.p 163-164° C.

[0296] Analysis. Calculated for C₁₅H₁₈N₄S: % C 62.91; % H, 6.34; % N,19.56. Found: % C 62.70; % H, 6.19; % N, 19.45 ¹H-NMR (300 MHz, DMSO) δ8.21 (s, 1H), δ 8.06 (d, J=8.3 Hz, 1H), δ 7.62 (d, J=8.3 Hz, 1H), δ 7.44(t, J=8.3 Hz, 1H), δ 7.26 (t, J=8.3 Hz, 1H), δ 6.59 (bs, 2H), δ 4.62 (t,J=7.6 Hz, 2H), δ 2.50 (t, J=6.8 Hz, 2H), δ 1.99 (s, 3H), δ 1.95 (p,J=7.3 Hz, 2H), δ 1.59 (p, J=7.3 Hz, 2H) MS (CI) for C₁₅H₁₈N₄S m/z 287(MH⁺), 185.

EXAMPLE 112-butyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0297]

Part A

[0298] Using the general method of Example 1 Part A,4-chloro-3-nitroquinoline (107.7 g, 525.87 mmol) was converted to5-[(3-nitroquinolin-4-yl)amino]pentan-1-ol using 5-amino-1-pentanol(79.82 g, 788.81 mmol) in lieu of 4-amino-butanol. The product (117.22g, 425.77 mmol) was used without further purification as a dark yellowsolid. MS (CI) for C₁₄H₁₇N₃O₃ m/z 276 (MH⁺), 224.

Part B

[0299] A round bottom flask was charged with a magnetic stir bar,5-[(3-nitroquinolin-4-yl)amino]pentan-1-ol (5.0 g, 18.16 mmol), andthionyl chloride (40.78 g, 0.34 mmol) under a nitrogen atmosphere. Thereaction mixture was heated to 80° C. to give a homogeneous solutionthat was maintained at 80° C. for 1 hour at which time the startingmaterial was completely consumed. The volatiles were removed underreduced pressure and the resulting oil stirred in water made basic (pH10) with solid sodium carbonate. The resulting solid was collected byfiltration to afford N-(5-chloropentyl)-3-nitroquinolin-4-amine (4.80 g,16.34 mmol) which was used without further purification.

Part C

[0300] Using the general method of Example 6 Part B, except that thereaction temperature was lowered to 80° C.,N-(5-chloropentyl)-3-nitroquinolin-4-amine (4.75 g, 16.17 mmol) wasconverted to N-[5-(methylthio)pentyl]-3-nitroquinolin-4-amine usingsodium thiomethoxide (1.43 g, 19.40 mmol) in lieu of sodiumbenzenethiolate. The product (3.28 g, 10.74 mmol) was isolated withoutfurther purification as a light yellow solid. MS (CI) for C₁₅H₁₉N₃O₂Sm/z 306 (MH⁺), 272, 117.

Part D

[0301] Using the general method of Example 1 Part C,N-[5-(methylthio)pentyl]-3-nitroquinolin-4-amine (3.20 g, 10.48 mmol)was reduced to N⁴-[5-(methylthio)pentyl]quinoline-3,4-diamine (2.89 g,10.48 mmol) which was isolated without further purification as a brownoil.

Part E

[0302] Using the general method of Example 1 Part D,N′-[5-(methylthio)pentyl]quinoline-3,4-diamine (2.89 g, 10.48 mmol) wascyclized to provide2-butyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinoline. Thematerial was purified by chromatography over silica gel (ethyl acetate)to afford the product (2.10 g, 6.15 mmol) as a light brown oil.

Part F

[0303] A round bottom flask was charged with a magnetic stir bar,2-butyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinoline (2.1 g, 6.15mmol) and chloroform (31 mL). Solid 3-chloroperbenzoic acid (4.41 g,19.68 mmol) was added portion wise to the solution over 10 minutes andthe reaction was stirred at ambient temperature for 30 minutes at whichtime the starting material was completely consumed. The solution waspartitioned between chloroform and saturated aqueous sodium bicarbonate.The layers were separated. The organic layer was washed with saturatedaqueous sodium bicarbonate and brine, dried over anhydrous sodiumsulfate, filtered and then concentrated under reduced pressure to afford2-butyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(2.40 g, 6.15 mmol) as a tan solid. The material was used withoutfurther purification.

Part G

[0304] Using the general method of Example 3 Part B,2-butyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(2.40 g, 6.15 mmol) was aminated to provide2-butyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine.The resulting solid (2.24 g) was dissolved in acetonitrile (40 mL) andbrought to reflux. Activated charcoal (1 g) was added and the resultingmixture was heated at reflux for 5 minutes and then the charcoal wasremoved by filtration through fluted paper to provide a light brownsolution. Upon cooling2-butyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine(0.90 g, 2.32 mmol) was isolated as white needles, m.p. 173-175° C.

[0305] Analysis. Calculated for C₂₀H₂₈N₄O₂S: % C 61.83; % H, 7.26; % N,14.42. Found: % C 61.58; % H, 7.27; % N, 14.36 ¹H-NMR (300 MHz, DMSO) δ8.01 (d, J=8.3 Hz, 1H), δ 7.61 (d, J=8.3 Hz, 1H), δ 7.41 (t, J=8.3 Hz,1H), δ 7.26 (t, J=8.3 Hz, 1H), δ 6.45 (bs, 2H), δ 4.51 (t, J=7.6 Hz,2H), δ 3.10 (t, J=7.8 Hz, 2H), δ 2.92 (s, 3H), δ 2.92 (t, J=7.3 Hz, 2H),δ 1.76 (m, 6H), δ 1.54 (m, 2H), δ 1.46 (sextet, J=7.3 Hz, 2H), δ 0.99(t, J=7.3 Hz, 3H) MS (CI) for C₂₀H₂₈N₄O₂S m/z 389 (MH⁺).

EXAMPLE 122-methyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0306]

Part A

[0307] Using the general method of Example 1 Part D,N⁴-[5-(methylthio)pentyl]quinoline-3,4-diamine (4.53 g, 16.37 mmol) wascyclized to provide2-methyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinoline using1,1,1-trimethoxyethane (2.95 g, 24.6 mmol) and pyridine hydrochloride(0.1 g). The material was triturated with ethyl ether and collected byfiltration to afford the product (3.78 g, 12.62 mmol) as a light brownsolid which was used without further purification.

Part B

[0308] Using the general method of Example 11 Part F,2-methyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinoline (3.78 g,12.62 mmol) was oxidized to2-methyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(4.38 g, 12.62 mmol) which was isolated as a tan solid and used withoutpurification.

Part C

[0309] Using the general method of Example 3 Part B,2-methyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(4.38 g, 12.62 mmol) was aminated to provide2-methyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine.The resulting solid was triturated with acetonitrile and collected byfiltration to afford the title compound (0.8 g, 2.31 mmol) as anoff-white solid, m.p. 235-240° C.

[0310] Analysis. Calculated for C₁₇H₂₂N₄O₂S: % C 58.94; % H, 6.40; % N,16.17. Found: % C 58.77; % H, 6.34; % N, 16.39 ¹H-NMR (300 MHz, DMSO) δ8.02 (d, J=8.3 Hz, 1H), δ 7.60 (d, J=8.3 Hz, 1H), δ 7.41 (t, J=8.3 Hz,1H), δ 7.25 (t, J=8.3 Hz, 1H), δ 6.49 (bs, 2H), δ 4.50 (t, J=7.3 Hz,2H), δ 3.12 (t, J=7.8 Hz, 2H), δ 2.92 (s, 3H), δ 2.61 (s, 3H), δ 1.86(m, 2H), δ 1.74 (m, 2H), δ 1.53 (m, 2H) MS (CI) for C₁₇H₂₂N₄O₂S m/z 347(MH⁺), 267.

EXAMPLE 13 2-ethyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0311]

Part A

[0312] Using the general method of Example 1 Part D,N4-[5-(methylthio)pentyl]quinoline-3,4-diamine (4.53 g, 16.37 mmol) wascyclized to 2-ethyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinolineusing triethyl orthopropionate (4.3 g, 24.56 mmol) and pyridinehydrochloride (0.1 g). The material was triturated with ethyl ether andcollected by filtration to afford the product (3.25 g, 10.37 mmol) as anoff-white powder which was used without further purification.

Part B

[0313] Using the general method of Example 11 Part F,2-ethyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinoline (3.25 g,10.37 mmol) was oxidized to2-ethyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(3.75 g, 10.37 mmol); which was isolated as a tan solid and used withoutpurification.

Part C

[0314] Using the general method of Example 3 Part B,2-ethyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(3.75 g, 10.37 mmol) was aminated to provide2-ethyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine.The resulting solid was recrystallized sequentially from ethanol andacetonitrile to afford the title compound (1.4 g, 3.88 mmol) asoff-white needles, m.p. 189-191° C. Analysis. Calculated forC₁₈H₂₄N₄O₂S: % C 59.98; % H, 6.71; % N, 15.54. Found: % C 59.71; % H,6.68; % N, 15.64 ¹H-NMR (300 MHz, DMSO) δ 8.01 (d, J=8.3 Hz, 1H), δ 7.61(d, J=8.3 Hz, 1H), δ 7.42 (t, J=8.3 Hz, 1H), δ 7.26 (t, J=8.3 Hz, 1H), δ6.45 (bs, 2H), δ 4.50 (t, J=7.6 Hz, 2H), δ 3.10 (t, J=7.8 Hz, 2H), δ2.95 (q, J=7.3 Hz, 2H), δ 2.92 (s, 3H), δ 1.85 (m, 2H), δ1.74 (m, 2H), δ1.55 (m, 2H), δ 1.38 (t, J=7.3 Hz, 3H) MS (CI) for C₁₈H₂₄N₄O₂S m/z 361(MH⁺), 281.

EXAMPLE 141-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0315]

Part A

[0316] Using the general method of Example 1 Part D,N4-[5-(methylthio)pentyl]quinoline-3,4-diamine (4.53 g, 16.37 mmol) wascyclized to 1-[5-(methylthio)pentyl)-1H-imidazo[4,5-c]quinoline usingtriethyl orthoformate (3.64 g, 24.56 mmol) and pyridine hydrochloride(0.1 g). The product (4.05 g, 14.19 mmol) was isolated as a brown oiland used without further purification.

Part B

[0317] Using the general method of Example 11 Part F,1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinoline (4.05 g, 14.19 mmol)was oxidized to1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-5N-oxide (4.73g, 14.19 mmol) which was isolated as a tan solid and used withoutfurther purification.

Part C

[0318] Using the general method of Example 3 Part B,1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-5N-oxide (4.73g, 14.19 mmol) was aminated to provide1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine. Thematerial was purified by chromatography over silica gel (95/5dichloromethane/methanol) to afford a light yellow solid. The solid wasrecrystallized from dimethyl formamide to give the title compound (0.43g, 1.29 mmol) as a light yellow, granular solid, m.p. 199-201° C.

[0319] Analysis. Calculated for C₁₆H₂₀N₄O₂S: % C 57.70; % H, 6.06; % N,16.85. Found: % C 57.01; % H, 6.06; % N, 16.70 ¹H-NMR (300 MHz, DMSO) δ8.20 (S, 1H), δ 8.04 (d, J=8.3 Hz, 1H), δ 7.62 (d, J=8.3 Hz, 1H), δ 7.44(t, J=8.3 Hz, 1H), δ 7.27 (t, J=8.3 Hz, 1H), δ 6.57 (bs, 2H), δ 4.61 (t,J=6.8 Hz, 2H), δ 3.09 (t, J=7.8 Hz, 2H), δ 2.92 (s, 3H), δ 1.91 (p,J=7.6 Hz, 2H), δ 1.73 (m, 2H), δ 1.45 (m, 2H) MS (CI) for C₁₆H₂₀N₄O₂Sm/z 333 (MH⁺).

EXAMPLE 152-hexyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0320]

Part A

[0321] A round bottom flask was charged with a magnetic stir bar,N⁴-[5-(methylthio)pentyl]quinoline-3,4-diamine (3.17 g, 11.46 mmol) andanhydrous pyridine (46 mL) under a nitrogen atmosphere. The resultinghomogeneous solution was cooled to 0° C. in an ice-water bath. To thecooled solution was added neat heptanoyl chloride (1.87 g, 12.61 mmol).The reaction was judged to be complete after stirring at ambienttemperature for 1 hour. The volatiles were removed under reducedpressure and the resulting oil was partitioned between chloroform andwater. The layers were separated. The organic layer was washed withsaturated aqueous sodium bicarbonate and brine, dried over anhydroussodium sulfate, filtered and then concentrated under reduced pressure toafford N-(4-{[5-(methylthio)pentyl]amino}quinolin-3-yl)heptanamide (4.44g, 11.46 mmol) which was isolated as a brown oil and used withoutfurther purification.

Part B

[0322] A round bottom flask was charged with a magnetic stir bar,N-(4-{[5-(methylthio)pentyl]amino}quinolin-3-yl)heptanamide (4.44 g,11.46 mmol), pyridine hydrochloride (0.13 g, 1.15 mmol), and anhydrouspyridine (50 mL) under a nitrogen atmosphere. The reaction was judged tobe complete after stirring at reflux for 1.5 hours. The solution wascooled and partitioned between ethyl acetate and water. The layers wereseparated. The organic layer was washed with saturated aqueous sodiumbicarbonate and brine, dried over anhydrous sodium sulfate, filtered andthen concentrated under reduced pressure to afford2-hexyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinoline (4.0 g,10.82 mmol) as a brown oil which was used without further purification.

Part C

[0323] Using the general method of Example 11 Part F,2-hexyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinoline (4.0 g,10.82 mmol) was oxidized to2-hexyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(4.52 g, 10.82 mmol) which was isolated as a tan solid and used withoutfurther purification.

Part D

[0324] Using the general method of Example 3 Part B2-hexyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(4.0 g, 10.82 mmol) was aminated to provide2-hexyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine.The material was recrystallized from acetonitrile to afford the titlecompound (2.25 g, 5.40 mmol) as off-white needles, m.p. 168-171° C.

[0325] Analysis. Calculated for C₂₂H₃₂N₄O₂S: % C 63.43; % H, 7.74; % N,13.45. Found: % C 63.06; % H, 7.66; % N, 13.81 ¹H-NMR (300 MHz, DMSO) δ8.01 (d, J=8.3 Hz, 1H), δ 7.62 (d, J=8.3 Hz, 1H), δ 7.42 (t, J=8.3 Hz,1H), δ 7.26 (t, J=8.3 Hz, 1H), δ 6.51 (bs, 2H), δ 4.51 (t, J=7.3 Hz,2H), δ 3.10 (t, J=7.8 Hz, 2H), δ 2.93 (s, 3H), δ 2.93 (t, J=7.3 Hz, 2H),δ 1.71-1.87 (m, 6H), δ 1.54 (m, 2H), δ 1.44 (m, 2H), δ 1.33 (m, 4H), δ0.89 (t, J=7.3 Hz, 3H) MS (CI) for C₂₂H₃₂N₄O₂S m/z 417 (M⁺), 337.

EXAMPLE 162-(2-methoxyethyl)-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0326]

Part A

[0327] A round bottom flask was charged with a magnetic stir bar,N⁴-[5-(methylthio)pentyl]quinoline-3,4-diamine (3.56 g, 12.93 mmol) andanhydrous pyridine (52 mL) under a nitrogen atmosphere. The resultinghomogeneous solution was cooled to 0° C. in an ice-water bath. To thecooled solution was added neat 3-methoxypropionyl chloride (2.74 g,22.36 mmol). After addition of the acid chloride, the reaction washeated to reflux for 14 hours at which time the acylated intermediatewas completely consumed. The solution was cooled and then partitionedbetween chloroform and saturated aqueous ammonium chloride. The layerswere separated. The organic layer was washed with saturated aqueoussodium bicarbonate, dried over anhydrous sodium sulfate, filtered andthen concentrated under reduced pressure to afford2-(2-methoxyethyl)-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinoline(3.0 g, 8.73 mmol) which was isolated as a brown oil and used withoutfurther purification.

Part B

[0328] Using the general method of Example 11 Part F,2-(2-methoxyethyl)-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinoline(3.0 g, 8.73 mmol) was oxidized to2-(2-methoxyethyl)-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(3.41 g, 8.73 mmol) which was isolated as a tan solid and used withoutfurther purification.

Part C

[0329] Using the general method of Example 3 Part B,2-(2-methoxyethyl)-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(3.41 g, 8.73 mmol) was aminated to provide2-(2-methoxyethyl)-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine.The resulting solid was purified by chromatography over silica gel (95/5dichloromethane/methanol) to provide a gummy solid. The solid wasrecrystallized from acetonitrile to give the title compound (0.54 g,1.38 mmol) as an off-white powder, m.p. 158-160° C.

[0330] Analysis. Calculated for C₁₉H₂₆N₄O₃S: % C 58.44; % H, 6.71; % N,14.35. Found: % C 58.24; % H, 6.76; % N, 14.70 ¹H-NMR (300 MHz, DMSO) δ8.02 (d, J=8.3 Hz, 1H), δ 7.62 (d, J=8.3 Hz, 1H), δ 7.42 (t, J=8.3 Hz,1H), δ 7.26 (t, J=8.3 Hz, 1H), δ 6.50 (bs, 2H), δ 4.53 (t, J=7.6 Hz,2H), δ 3.83 (t, J=6.8 Hz, 2H), δ 3.30 (s, 3H), δ 3.19 (t, J6.8Hz, 2H), δ3.11 (t, J=7.8 Hz, 2H), δ 2.93 (s, 3H), δ 1.85 (m, 2H), δ 1.76 (m, 2H),δ 1.57 (m, 2H) MS (CI) for C₁₉H₂₆N₄O₃S m/z 391 (MH⁺), 359.

EXAMPLE 172-butyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0331]

Part A

[0332] Using the general method of Example 1 Part C,N-(5-chloropentyl)-3-nitroquinolin-4-amine (2.0 g, 6.80 mmol) wasreduced to provide N-(5-chloropentyl)quinoline-3,4-diamine (1.79 g, 6.80mmol) which was isolated as a brown oil and used without furtherpurification.

Part B

[0333] Using the general method of Example I Part D,N⁴-(5-chloropentyl)quinoline-3,4-diamine (1.79 g, 6.80 mmol) wascyclized to 2-butyl-1-(5-chloropentyl)-1H-imidazo[4,5-c]quinoline usingtrimethyl orthovalerate (2.55 g, 15.72 mmol) and pyridine hydrochloride(0.079 g). The product (1.95 g, 5.91 mmol) was isolated as an off-whitesolid and used without further purification.

Part C

[0334] Using the general method of Example 1 Part E,2-butyl-1-(5-chloropentyl)-1H-imidazo[4,5-c]quinoline (1.95 g, 5.91mmol) was oxidized to2-butyl-1-(5-chloropentyl)-1H-imidazo[4,5-c]quinoline-5N-oxide (2.04 g,5.91 mmol) which was isolated as a tan solid and used without furtherpurification.

Part D

[0335] Using the general method of Example 3 Part B,2-butyl-1-(5-chloropentyl)-1H-imidazo[4,5-c]quinoline-5N-oxide (2.04 g,5.91 mmol) was aminated to provide2-butyl-1-(5-chloropentyl)-1H-imidazo[4,5-c]quinolin-4-amine. Theresulting solid was recrystallized from ethanol to afford the product(0.85 g, 2.46 mmol) as a fine white powder, m.p. 144-146° C.

[0336] Analysis. Calculated for C₁₉H₂₅CIN₄: % C 66.17; % H, 7.31; % N,16.24. Found: % C 66.44; % H, 7.55; % N, 16.29 MS (CI) for C₁₉H₂₅CIN₄m/z 345 (MH⁺), 309.

Part E

[0337] Using the general method of Example 6 Part B, except that thereaction temperature was lowered to 80° C.,2-butyl-1-(5-chloropentyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g,5.80 mmol) was converted to2-butyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine usingsodium thiomethoxide (0.68 g, 8.70 mmol) in lieu of sodiumbenzenethiolate. The resulting solid was partitioned between chloroformand saturated aqueous sodium bicarbonate. The layers were separated. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and then concentrated under reduced pressure to afforda white solid. The material was recrystallized from acetonitrile to givethe title compound (1.91 g, 5.36 mmol) as a fine white solid, m.p.112-114° C.

[0338] Analysis. Calculated for C₂₀H₂₈N₄S: % C 67.38; % H, 7.92; % N,15.71. Found: % C 67.26; % H, 8.08; % N, 15.74 ¹H-NMR (300 MHz, DMSO) δ8.01 (d, J=8.3 Hz, 1H), δ 7.61 (d, J=8.3 Hz, 1H), δ 7.41 (t, J=8.3 Hz,1H), δ 7.25 (t, J=8.3 Hz, 1H), δ 6.45 (bs, 2H), δ 4.50 (t, J=7.8 Hz,2H), δ 2.92 (t, J=7.6 Hz, 2H), δ 2.46 (t, J=7.3 Hz, 2H), δ 2.01 (s, 3H),δ 1.80 (m, 4H), δ 1.42-1.61 (m, 6H), δ 0.96 (t, J=7.3 Hz, 3H) MS (CI)for C₂₀H₂₈N₄S m/z 357 (MH⁺), 309.

Example 182-butyl-1-[5-(methylsulfinyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0339]

[0340] A round bottom flask was charged with a magnetic stir bar,2-butyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.0g, 2.80 mmol) and chloroform (14 mL). Solid 3-chloroperbenzoic acid(0.69 g, 3.09 mmol) was added portion wise over 5 minutes and thereaction was stirred at ambient temperature for 20 minutes at which timethe starting material was completely consumed. The solution waspartitioned between chloroform and saturated aqueous sodium bicarbonate.The layers were separated. The organic layer was washed with saturatedaqueous sodium bicarbonate and brine, dried over anhydrous sodiumsulfate, filtered and then concentrated under reduced pressure to affordan off-white solid which was shown by ¹H-NMR to be the 3-chlorobenzoicacid salt of the desired product. The solid was stirred in water andthen made basic (pH 10) by addition of solid sodium carbonate. Theresulting free base was collected by filtration to provide a white solidwhich was recrystallized from acetonitrile to give2-butyl-1-[5-(methylsulfinyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine(0.40 g, 1.07 mmol) as a white powder, m.p. 119-121° C.

[0341] Analysis. Calculated for C₂₀H₂₈N₄OS (H₂O)₁: % C 61.51; % H, 7.74;% N, 14.35. Found: % C 61.64; % H, 7.82; % N, 14.32 ¹H-NMR (300 MHz,DMSO) δ 8.01 (d, J=8.3 Hz, 1H), δ 7.60 (d, J=8.3 Hz, 1H), δ 7.41 (t,J=8.3 Hz, 1H), δ 7.26 (t, J=8.3 Hz, 1H), δ 6.44 (bs, 2H), δ 4.51 (t,J=7.6 Hz, 2H), δ 2.92 (t, J=7.8 Hz, 2H), δ 2.57-2.74 (m, 2H), δ 2.50 (s,3H), δ 1.80 (m, 4H), 1.66 (m, 2H), δ 1.55 (m, 2H), δ 1.48 (m, 2H), δ0.96 (t, J=7.3 Hz, 3H) MS (CI) for C₂₀H₂₈N₄OS (H₂O)₁ m/z 373 (MH⁺), 309,253.

EXAMPLE 192-butyl-1-[3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0342]

Part A

[0343] A round bottom flask was charged with a magnetic stir bar,3-[(3-nitroquinolin-4-yl)amino]propan-1-ol (20.75 g, 83.93 mmol),thionyl chloride (15.0 g, 125.89 mmol), and dichloromethane (420 mL).The bright yellow, homogeneous solution was stirred at ambienttemperature for 2 hours at which time the starting material wascompletely consumed. The volatiles were removed under reduced pressureand the resulting solid stirred in water (400 mL) made basic (pH 10)with solid sodium carbonate. A bright yellow solid was collected byfiltration to afford N-(3-chloropropyl)-3-nitroquinolin-4-amine (21.63g, 81.41 mmol) which was used without further purification.

Part B

[0344] Using the general method of Example 1 Part C,N-(3-chloropropyl)-3-nitroquinolin-4-amine (10.0 g, 37.63 mmol) wasreduced to provide N⁴-(3-chloropropyl)quinoline-3,4-diamine (8.87 g,37.63 mmol) which was isolated as a brown oil and used without furtherpurification.

Part C

[0345] Using the general method of Example 1 Part D,N⁴-(3-chloropropyl)quinoline-3,4-diamine (8.87 g, 37.63 mmol) wascyclized to provide2-butyl-1-(3-chloropropyl)-1H-imidazo[4,5-c]quinoline using trimethylorthovalerate (7.33 g, 45.16 mmol) and pyridine hydrochloride (0.43 g).The resulting solid was triturated with ethyl ether and collected byfiltration to afford the product (9.00 g, 29.82 mmol) as an off-whitesolid. The material was used without further purification.

Part D

[0346] Using the general method of Example 1 Part E,2-butyl-1-(3-chloropropyl)-1H-imidazo[4,5-c]quinoline (9.0 g, 29.82mmol) was oxidized to2-butyl-1-(3-chloropropyl)-1H-imidazo[4,5-c]quinoline-5N-oxide (9.48 g,29.82 mmol) which was isolated as a tan solid and used withoutpurification.

Part E

[0347] Using the general method of Example 3 Part B,2-butyl-1-(3-chloropropyl)-1H-imidazo[4,5-c]quinoline-5N-oxide (9.48 g,29.82 mmol) was aminated to provide2-butyl-1-(3-chloropropyl)-1H-imidazo[4,5-c]quinolin-4-amine. Theresulting solid was purified by chromatography over silica gel (95/5dichloromethane/methanol) to provide the product (6.4 g, 20.20 mmol) asa tan solid.

Part F

[0348] Using the general method of Example 6 Part B, except that thereaction temperature was lowered to 80° C.,2-butyl-1-(3-chloropropyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g,6.31 mmol) was converted to2-butyl-1-[3-(methylthio)propyl]-1H-imidazo[4,5-c]quinolin-4-amine usingsodium thiomethoxide (0.74 g, 9.47 mmol) in lieu of sodiumbenzenethiolate. The resulting solid was partitioned between chloroformand saturated aqueous sodium bicarbonate. The layers were separated. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and then concentrated under reduced pressure to affordthe title compound (2.0 g, 6.09 mmol) as a white solid. The material wasused without further purification.

Part G

[0349] Using the general method of Example 5 Part A,2-butyl-1-[3-(methylthio)propyl]-1H-imidazo[4,5-c]quinolin-4-amine 2.0g, 6.09 mmol) was oxidized to2-butyl-1-[3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine.The resulting solid was triturated with methanol and collected byfiltration to afford the title compound (0.96 g, 2.66 mmol) as anoff-white powder, m.p. 233-236° C.

[0350] Analysis. Calculated for C₁₈H₂₄N₄O₂S: % C 59.98; % H, 6.71; % N,15.54. Found: % C 59.71; % H, 6.65; % N, 15.43 ¹H-NMR (300 MHz, DMSO) δ8.10 (d, J=8.3 Hz, 1H), δ 7.61 (d, J=8.3 Hz, 1H), δ 7.42 (t, J=8.3 Hz,1H), δ 7.25 (t, J=8.3 Hz, 1H), δ 6.47 (bs, 2H), δ 4.66 (t, J=7.8 Hz,2H), δ 3.40 (t, J=7.3 Hz, 2H), δ 3.01 (s, 3H), δ 2.94 (t, J=7.8 Hz, 2H),δ 2.22 (m, 2H), δ 1.80 (m, 2H), δ 1.46 (sextet, J=7.3 Hz, 2H), δ 0.96(t, J=7.3 Hz, 3H) MS (CI) for C₁₈H₂₄N₄O₂S m/z 361 (MH⁺), 281, 235.

EXAMPLE 202-butyl-1-[3-(phenylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0351]

Part A

[0352] A round bottom flask was charged with a magnetic stir bar,benzenethiol (0.68 g, 6.21 mmol), sodium hydride (0.25 g, 60%dispersion, 6.21 mmol), and anhydrous dimethyl formamide (28 mL) under anitrogen atmosphere. After the reaction mixture had stirred at ambienttemperature for 30 minutes,2-butyl-1-(3-chloropropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.64 g,5.18 mmol) was added and the resulting cloudy solution was heated to 80°C. and maintained at 80° C. for 2.5 hours at which time the startingmaterial was completely consumed. The hot solution was poured intorapidly stirred water (200 mL). The resulting mixture was extracted withchloroform (2×). The combined organic layers were washed with saturatedaqueous sodium bicarbonate and brine, dried over anhydrous sodiumsulfate, filtered and then concentrated under reduced pressure to afforda light yellow oil. The material was purified by chromatography oversilica gel (95/5 dichloromethane/methanol) to provide2-butyl-1-[3-(phenylthio)propyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.38g, 3.53 mmol) as a white solid.

Part B

[0353] Using the general method of Example 5 Part A,2-butyl-1-[3-(phenylthio)propyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.38g, 3.53 mmol) was oxidized to2-butyl-1-[3-(phenylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine.The resulting solid was recrystallized from ethanol to provide the titlecompound (0.85 g, 2.01 mmol) as an off-white powder, m.p. 224-227° C.

[0354] Analysis. Calculated for C₂₃H₂₆N₄O₂S: % C 65.38; % H, 6.20; % N,13.26. Found: % C 65.25; % H, 6.23; % N, 13.20 ¹H-NMR (300 MHz, DMSO) δ7.96 (d, J=8.3 Hz, 1H), δ 7.89 (m, 2H), δ 7.73 (m, 1H), δ 7.63 (m, 3H),δ 7.40 (t, J=8.3 Hz, 1H), δ 7.17 (t, J=8.3 Hz, 1H), δ 6.46 (bs, 2H), δ4.60 (t, J=7.8 Hz, 2H), δ 3.66 (t, J=7.3 Hz, 2H), δ 2.86 (t, J=7.8 Hz,2H), δ 2.04 (m, 2H), δ 1.73 (p, J=7.6 Hz, 2H), δ 1.39 (sextet, J=7.3 Hz,2H), δ 0.92 (t, J=7.3 Hz, 3H) MS (CI) for C₂₃H₂₆N₄O₂S m/z 423 (MH⁺),322, 281.

EXAMPLE 211-[5-(methylsulfonyl)pentyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine

[0355]

Part A

[0356] Using the general method of Example 1 Part D,N⁴-(5-chloropentyl)quinoline-3,4-diamine (˜20.4 mmol) was cyclized usingtrimethyl orthobutyrate (3.6 g, 24.5 mmol) in the presence of pyridinehydrochloride (˜0.1 g). The crude product was purified by columnchromatography (silica gel eluting with 95/5 dichloromethane/methanol)to provide 3.9 g of1-(5-chloropentyl)-2-propyl-1H-imidazo[4,5-c]quinoline as a light greensolid.

Part B

[0357] Using the general method of Example 1 Part E,1-(5-chloropentyl)-2-propyl-1H-imidazo[4,5-c]quinoline (3.9 g, 12.36mmol) was oxidized to provide1-(5-chloropentyl)-2-propyl-1H-imidazo[4,5-c]quinoline-5N-oxide as adark orange oil.

Part C

[0358] Using the general method of Example 3 Part B, the material fromPart B was aminated to provide1-(5-chloropentyl)-2-propyl-1H-imidazo[4,5-c]quinoline-4-amine. Thecrude product was slurried with diethyl ether, isolated by filtration,washed with diethyl ether and then dried to provide 3.42 g of theproduct as a white powder.

Part D

[0359] A suspension of1-(5-chloropentyl)-2-propyl-1H-imidazo[4,5-c]quinoline-4-amine (2.5 g,7.56 mmol) in anhydrous N,N-dimethylformamide (38 mL) was heated to 80°C. to provide a light yellow solution. Sodium thiomethoxide (0.67 g of95%, 9.07 mmol) was added in a single portion and heating was continuedfor 110 minutes. The resulting light brown suspension was poured intowater (300 mL) with rapid stirring. A white solid precipitated. Afterthe suspension had cooled to ambient temperature, several scoops ofsolid sodium carbonate were added. The suspension was chilled in an icewater bath with stirring for 1 hour. The solid was isolated byfiltration, washed with cold water and then dried to provide 2.3 g of1-[5-(methylthio)pentyl]-2-propyl-1H-imidazo[4,5-c]quinoline-4-amine asa white powder.

Part E

[0360] Using the general method of Example 5, the material from Part Dwas oxidized and the crude product purified to provide 0.88 g of1-[5-(methylsulfonyl)pentyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amineas a white powder, m.p. 179-181° C.

[0361] Analysis: Calculated for C₁₉H₂₆N₄O₂S: % C, 60.94; % H, 7.00; % N,14.96; Found: % C, 60.60; % H, 7.03; % N, 14.84. ¹H NMR (300 MHz,DMSO-d₆) δ 8.0 (d, J=7.8 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.41 (t,J=8.4, Hz, 1H), 7.25 (dt, J=8.1, 1.2 Hz, 1 H), 6.43 (s, 2 H), 4.50 (t,J=7.5 Hz, 2 H), 3.10 (t, J=8.1 Hz, 2 H), 2.92 (s, 3 H), 2.90 (m, 2 H),1.84 (quintet, J=7.5 Hz, 4 H), 1.74 (m, 2 H), 1.54 (quintet, J=8.1 Hz,2H), 1.04 (t, J=7.5 Hz, 3H); MS(CI) m/e 375 (M+H).

EXAMPLE 222-methyl-1-[3-(methylthio)propyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0362]

Part A

[0363] Using the general method of Example 1 Part D,N⁴-(3-chloropropyl)quinoline-3,4-diamine (˜37.6 mmol) was cyclized using1,1,1-trimethoxyethane (5.43 g, 45.2 mmol) in the presence of pyridinehydrochloride (0.43 g) to provide 7.6 g of1-(3-chloropropyl)-2-methyl-1H-imidazo[4,5-c]quinoline as a light yellowsolid.

Part B

[0364] Using the general method of Example 1 Part E,1-(3-chloropropyl)-2-methyl-1H-imidazo[4,5-c]quinoline (7.53 g, 29.0mmol) was oxidized to provide1-(3-chloropropyl)-2-methyl-1H-imidazo[4,5-c]quinoline-5N-oxide as a tansolid.

Part C

[0365] Using the general method of Example 3 Part B, the material fromPart B was aminated. The crude product was slurried with diethyl etherand then recrystallized from isopropanol to provide 3.7 g of1-(3-chloropropyl)-2-methyl-1H-imidazo[4,5-c]quinoline-4-amine as alight yellow powder.

Part D

[0366] Using the general method of Example 21 Part D, the material fromPart C was reacted with sodium thiomethoxide. The crude product wasrecrystallized from acetonitrile and then triturated with diethyl etherto provide 3.07 g of2-methyl-1-[3-(methylthio)propyl]-1H-imidazo[4,5-c]quinolin-4-amine asgold needles, m.p. 199-202° C.

[0367] Analysis: Calculated for C₁₅H₁₈N₄S: % C, 62.91; % H, 6.34; % N,19.56; Found: % C, 62.74; % H, 6.20; % N, 19.47. ¹H NMR (300 MHz,DMSO-d₆) δ 8.13 (d, J=7.5 Hz, 1 H), 7.61 (d, J=7.5 Hz, 1 H), 7.42 (t,J=7.2, Hz, 1 H), 7.24 (t, J=7.2, Hz, 1 H), 6.51 (s, 2 H), 4.58 (t, J=7.5Hz, 2 H), 2.67-2.61 (m, 5 H), 2.09 (m, 5 H); MS(CI) m/e 287 (M+H)

EXAMPLE 232-methyl-1-[3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0368]

[0369] Using the general method of Example 5,2-methyl-1-[3-(methylthio)propyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.8g, 6.28 mmol) was oxidized and the crude product purified to provide0.91 g of2-methyl-1-[3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, m.p. 225-228° C.

[0370] Analysis: Calculated for C₁₅H₁₈N₄O₂S: % C, 56.59; % H, 5.70; % N,17.60; Found: % C, 56.60; % H, 5.68; % N, 17.61. ¹H NMR (300 MHz,DMSO-d₆) δ 8.04 (d, J=8.1 Hz, 1 H), 7.61 (d, J=8.1 Hz, 1 H), 7.43 (t,J=7.2, Hz, 1 H), 7.25 (dt, J=6.9, 1.2, Hz, 1 H), 6.56 (s, 2 H), 4.65 (t,J=7.8 Hz, 2 H), 3.38 (t, J=7.8 Hz, 2 H), 3.01 (s, 3 H), 2.62.(s, 3 H),2.24 (quintet, J=7.5 Hz, 2 H); MS(CI) m/e 319 (M+H).

EXAMPLE 242-ethyl-1-[3-(methylthio)propyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0371]

Part A

[0372] Using the general method of Example 1 Part D,N⁴-(3-chloropropyl)quinoline-3,4-diamine (˜37.6 mmol) was cyclized usingtriethyl orthopropionate (7.96 g, 45.2 mmol) in the presence of pyridinehydrochloride (0.43 g). The crude product was purified by chromatography(silica gel eluting with 95/5 dichloromethane/methanol) to provide 7.33g of 1-(3-chloropropyl)-2-ethyl-1H-imidazo[4,5-c]quinoline as a whitesolid.

Part B

[0373] Using the general method of Example 1 Part E,1-(3-chloropropyl)-2-ethyl-1H-imidazo[4,5-c]quinoline (7.33 g, 26.8mmol) was oxidized to provide1-(3-chloropropyl)-2-ethyl-1H-imidazo[4,5-c]quinoline-5N-oxide as asolid.

Part C

[0374] Using the general method of Example 3 Part B, the material fromPart B was aminated. The crude product was slurried with diethyl etherto provide 6.2 g of1-(3-chloropropyl)-2-ethyl-1H-imidazo[4,5-c]quinoline-4-amine as a whitepowder.

Part D

[0375] Using the general method of Example 21 Part D,1-(3-chloropropyl)-2-ethyl-1H-imidazo[4,5-c]quinoline-4-amine (4.0 g,13.85 mmol) was reacted with sodium thiomethoxide (1.53 g, 20.78 mmol).The crude product was triturated with diethyl ether to provide 3.65 g ofa white powder. A portion (1.5 g) was purified by chromatography (silicagel eluting with 95/5 dichloromethane/methanol) to provide 1 g of2-ethyl-1-[3-(methylthio)propyl]-1H-imidazo[4,5-c]quinolin-4-amine as awhite powder, m.p. 210-212° C.

[0376] Analysis: Calculated for C₁₆H₂₀N₄S: % C, 63.97; % H, 6.71; % N,18.65; Found: % C, 63.70; % H, 6.59; % N, 18.62. ¹H NMR (300 MHz,DMSO-d₆) δ 8.14 (d, J=8.7 Hz, 1 H), 7.62 (dd, J=6.9, 1.2 Hz, 1 H), 7.42(dt, J=7.2, 1.2 Hz, 1 H), 7.25 (dt, J=6.9, 1.2, Hz, 1 H), 6.48 (s, 2 H),4.58 (t, J=7.5 Hz, 2 H), 2.97 (quartet, J=7.5 Hz, 2 H), 2.65 (t, J=6.9Hz, 2 H), 2.12-2.02 (m, 5 H), 1.38 (t, J=7.5 Hz, 3H); MS(CI) m/e 301(M+H).

EXAMPLE 252-ethyl-1-[3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0377]

[0378] Using the general method of Example 5,2-ethyl-1-[3-(methylthio)propyl]-1H-imidazo[4,5-c]quinolin-4-amine (2.1g, 6.99 mmol) was oxidized to provide 1.7 g of2-ethyl-1-[3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amineas a fine white powder, m.p. >250° C.

[0379] Analysis: Calculated for C₁₆H₂₀N₄O₂S: % C, 57.81; % H, 6.06; % N,16.85; Found: % C, 57.81; % H, 5.88; % N, 16.78. ¹H NMR (300 MHz,DMSO-d₆) δ 8.12 (d, J=8.1 Hz, 1 H), 7.62 (d, J 8.1 Hz, 1 H), 7.43 (t,J=8.1, Hz, 1 H), 7.25 (t, J=8.4, Hz, 1 H), 6.45 (s, 2 H), 4.65 (t, J=7.8Hz, 2 H), 3.39 (t, J=7.8 Hz, 2 H), 3.00 (s, 3 H), 2.96 (quartet, J=7.2Hz, 2 H), 2.22 (quintet, J=7.8 Hz, 2 H), 1.38 (t, J=7.2Hz, 3 H); MS(CI)m/e 333 (M+H).

EXAMPLE 262-methyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0380]

Part A

[0381] Using the general method of Example 19 Part A,4-[(3-nitroquinolin-4-yl)amino]butan-1-ol (120 g, 0.459 mol) waschlorinated with thionyl chloride (109 g, 0.919 mol) to provide 127.9 gof N-(4-chlorobutyl)-3-nitroquinolin-4-amine as a yellow powder.

Part B

[0382] Using the general method of Example 1 Part C,N-(4-chlorobutyl)-3-nitroquinolin-4-amine (7.0 g, 25.0 mmol) was reducedto provide N⁴-(4-chlorobutyl)quinoline-3,4-diamine as a dark brown oil.

Part C

[0383] Using the general method of Example 1 Part D, the material fromPart B was cyclized using 1,1,1-trimethoxyethane (3.6 g, 30.12 mmol) inthe presence of pyridine hydrochloride (0.29 g) to provide 7.6 g of1-(4-chlorobutyl)-2-methyl-1H-imidazo[4,5-c]quinoline as a dark brownoil.

Part D

[0384] Using the general method of Example 1 Part E,1-(4-chlorobutyl)-2-methyl-1H-imidazo[4,5-c]quinoline (5.8 g of thematerial from Part C) was oxidized to provide ˜6.33 g of1-(4-chlorobutyl)-2-methyl-1H-imidazo[4,5-c]quinoline-5N-oxide as anamber oil.

Part E

[0385] Using the general method of Example 3 Part B, the material fromPart D was aminated and purified to provide 1.84 g of1-(4-chlorobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine as anoff-white fluffy powder.

Part F

[0386] Using the general method of Example 21 Part D, the material fromPart E was reacted with sodium thiomethoxide. The crude product wasrecrystallized from 1,2-dichloroethane and then triturated with diethylether to provide 1.21 g of2-methyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine as awhite powder, m.p. 190-193° C.

[0387] Analysis: Calculated for C₁₆H₂₀N₄S: % C, 63.97; % H, 6.71; % N,18.65; Found: % C, 63.77; % H, 6.65; % N, 18.55. ¹H NMR (300 MHz,DMSO-d₆) δ 8.05 (d, J=8.1 Hz, 1 H), 7.60 (d, J=9.3 Hz, 1 H), 7.41 (t,J=8.4 Hz, 1 H), 7.24 (t, J=8.4 Hz, 1 H), 6.48 (s, 2 H), 5.42 (t, J=7.41(s, 3 H), 2.53 (m, 2 H), 2.02 (s, 3 H), 1.91 (quintet, J=7.5 Hz, 2 H),1.69 (quintet, J=7.5 Hz, 2 H); MS(CI) m/e 301 (M+H).

EXAMPLE 272-methyl-1-[4-(methylsulfinyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0388]

[0389] Using the general method of Example 18,2-methyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (2.15g, 7.16 mmol) was oxidized to provide the crude sulfoxide. This materialwas purified by sequentially recrystallizing from acetonitrile,chromatographing (silica gel eluting with 90/10dichloromethane/methanol) and triturating with diethyl ether to provide0.7 g of2-methyl-1-[4-(methylsulfinyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amineas a white powder, m.p. 184-187° C.

[0390] Analysis: Calculated for C₁₆H₂₀N₄OS: % C, 60.73: % H, 6.37; % N,17.71; Found: % C, 60.37; % H, 6.38; % N, 17.52. ¹H NMR (300 MHz,DMSO-d₆) δ 8.04 (d, J=8.1 Hz, 1 H), 7.61 (d, J=8.1 Hz, 1 H), 7.42 (dt,J=6.9, 1.3 Hz, 1 H), 7.26 (dt, J=6.9, 1.3, Hz, 1 H), 6.53 (s, 2 H), 4.55(t, J=7.2 Hz, 2 H), 2.87-2.66 (m, 2 H), 2.67 (s, 3 H), 2.51 (s, 3 H),1.95 (m, 2 H), 1.81 (quintet, J=7.5 Hz, 2 H); MS(CI) m/e 317 (M+H).

EXAMPLE 282-ethyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0391]

Part A

[0392] Using the general method of Example 1 Part D,N⁴-(4-chlorobutyl)quinoline-3,4-diamine (˜35.75 mmol) was cyclized usingtriethyl orthopropionate (7.56 g, 42.9 mmol) in the presence of pyridinehydrochloride (0.41 g). The crude product was purified by chromatography(silica gel eluting with 95/5 dichloromethane/methanol) to provide 7.5 gof 1-(4-chlorobutyl)-2-ethyl-1H-imidazo[4,5-c]quinoline as a whitepowder.

Part B

[0393] Using the general method of Example 1 Part E, the material fromPart A was oxidized to provide1-(4-chlorobutyl)-2-ethyl-1H-imidazo[4,5-c]quinoline-5N-oxide as a tansolid.

Part C

[0394] Using the general method of Example 3 Part B, the material fromPart B was aminated and purified to provide 7.0 g of1-(4-chlorobutyl)-2-ethyl-1H-imidazo[4,5-c]quinoline-4-amine as a whitepowder.

Part D

[0395] Using the general method of Example 21 Part D, the material fromPart C was reacted with sodium thiomethoxide. The crude product wasrecrystallized from isopropanol and then triturated with diethyl etherto provide 1.55 g of2-ethyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine as awhite powder, m.p. 183-186° C.

[0396] Analysis: Calculated for C₁₇H₂₂N₄S: % C, 64.93; % H, 7.05; % N,17.82; Found: % C, 65.07; % H, 7.17; % N, 17.66. ¹H NMR (300 MHz,DMSO-d6) δ 8.04 (d, J=7.5 Hz, 1 H), 7.61 (dd, J=9.3, 1.5 Hz, 1 H), 7.41(dt, J=7.8, 1.4 Hz, 1 H), 7.25 (dt, J=7.5, 1.5 Hz, 1 H), 6.44 (s, 2 H),4.52 (t, J=7.50 Hz, 2 H), 2.95 (quartet, J=7.5 Hz, 2 H), 2.55 (m, 2 H),2.02 (s, 3 H), 1.90 (m, 2 H), 1.71 (m, 2 H), 1.38 (t, J=7.2Hz, 3 H);MS(CI) m/e 315 (M+H).

EXAMPLE 292-ethyl-1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0397]

[0398] Using the general method of Example 5,2-ethyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (2.3g, 7.31 mmol) was oxidized. The crude product was sequentiallytriturated with diethyl ether, chromatographed (silica gel eluting with90/10 dichloromethane/methanol), recrystallized from ethanol andtriturated with diethyl ether to provide 1.18 g of2-ethyl-1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine asa white powder, m.p. 182-185° C.

[0399] Analysis: Calculated for C₁₇H₂₂N₄O₂S: % C, 58.94; % H, 6.40; % N,16.17; Found: % C, 58.89; % H, 6.51; % N, 16.13. ¹H NMR (300 MHz,DMSO-d₆) δ 8.04 (d, J=8.1 Hz, 1 H), 7.62 (dd, J=8.1, 1.5 Hz, 1 H), 7.42(dt, J=6.9, 1.2 Hz, 1 H), 7.26 (t, J=7.4 Hz, 1 H), 6.45 (s, 2 H), 4.55(t, J=7.05 Hz, 2 H), 3.21 (t, J=7.2Hz, 2 H), 2.96 (m, 5 H), 1.91 (m, 4H), 1.38 (t, J=7.2Hz, 3 H); MS(CI) m/e 347 (M+H).

EXAMPLE 301-[4-(methylsulfonyl)butyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine

[0400]

Part A

[0401] Using the general method of Example 1 Part D,N4-(4-chlorobutyl)quinoline-3,4-diamine (˜21.45 mmol) was cyclized usingtrimethyl orthobutyrate (3.8 g, 25.74 mmol) in the presence of pyridinehydrochloride (0.1 g). The crude product was purified by chromatography(silica gel eluting with 95/5 dichloromethane/methanol) to provide 3.6 gof 1-(4-chlorobutyl)-2-propyl-1H-imidazo[4,5-c]quinoline as a lightgreen oil which slowly solidified.

Part B

[0402] Using the general method of Example 1 Part E, the material fromPart A was oxidized to provide1-(4-chlorobutyl)-2-propyl-1H-imidazo[4,5-c]quinoline-5N-oxide as alight orange oil.

Part C

[0403] Using the general method of Example 3 Part B, the material fromPart B was aminated and purified to provide 3.0 g of1-(4-chlorobutyl)-2-propyl-1H-imidazo[4,5-c]quinoline-4-amine as anoff-white solid.

Part D

[0404] Using the general method of Example 21 Part D, the material fromPart C was reacted with sodium thiomethoxide to provide 2.52 g of1-[4-(methylthio)butyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as asolid.

Part E

[0405] Using the general method of Example 5, the material from part Dwas oxidized. The crude product was sequentially chromatographed (silicagel eluting with 95/5 dichloromethane/methanol), recrystallized fromethanol and triturated with diethyl ether to provide 1.15 g of a solid.This material was dissolved in hot N,N-dimethylformamide (6 mL) and thesolution was poured into water (100 mL). The resulting precipitate wasisolated by filtration, washed with water and dried to obtain 1.0 g of1-[4-(methylsulfonyl)butyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amineas an off-white powder, m.p. 202-204° C.

[0406] Analysis: Calculated for C₁₈H₂₄N₄O₂S: % C, 59.98; % H, 6.71; % N,15.54; Found: % C, 59.71; % H, 6.69; % N, 15.41. ¹H NMR (300 MHz,DMSO-d6) δ 8.03 (d, J=8.1 Hz, 1 H), 7.61 (dd, J=8.1, 1.2 Hz, 1 H), 7.42(dt, J=7.2, 1.2, Hz, 1 H), 7.26 (t, J=7.5, Hz, 1 H), 6.44 (s, 2 H), 4.55(t, J=6.5 Hz, 2 H), 3.21 (t, J=7.2 Hz, 2 H), 2.96 (s, 3 H), 2.91 (t,J=7.5 Hz, 2 H), 1.92-1.79 (m, 6H), 1.04 (t, J=7.5Hz, 3 H); MS(CI) m/e361 (M+H).

EXAMPLE 312-butyl-1-[4-(methylsulfinyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0407]

[0408] Using the general method of Example 18,2-butyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (2.5g, 7.30 mmol) was oxidized and purified to provide 1.5 g of2-butyl-1-[4-(methylsulfinyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine asa white solid, m.p. 126-128° C.

[0409] Analysis: Calculated for C₁₉H₂₆N₄OS.0.25 H₂O: % C, 62.87; % H,7.36; % N, 15.43; Found: % C, 62.57; % H, 7.34; % N, 15.47. ¹H NMR (300MHz, DMSO-d₆) δ 8.03 (d, J=8.1 Hz, 1 H), 7.61 (d, J=9.0 Hz, 1 H), 7.41(t, J=6.9 Hz, 1 H), 7.25 (t, J=7.1, Hz, 1 H), 6.46 (s, 2 H), 4.56 (t,J=7.3 Hz, 2 H), 2.93 (t, J=7.8 Hz, 2 H), 2.87-2.66 (m, 2 H), 2.51 (s, 3H), 1.93-1.75 (m, 6 H), 1.46 (sextet, J=7.5 Hz, 2 H), 0.96 (t, J=7.4 Hz,3 H); MS(CI) m/e 359 (M+H).

EXAMPLE 322-methyl-1-[2-(methylthio)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0410]

Part A

[0411] Using the general method of Example 6 Part A except that asolvent (55 mL of 1,2-dichloroethane) was included,2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (4.0 g, 16.51mol) was chlorinated using thionyl chloride (2.41 mL, 33.02 mmol) toprovide 3.9 g of1-(2-chloroethyl)-2-methyl-1H-imidazo[4,5-c]quinoline-4-amine as a fine,white powder.

Part B

[0412] Using the general method of Example 21 Part D,1-(2-chloroethyl)-2-methyl-1H-imidazo[4,5-c]quinoline-4-amine (3.75 g,14.38 mmol) was reacted with sodium thiomethoxide (1.6 g, 21.57 mmol) toprovide 3.2 g of the thioether as an off-white solid. A portion (1.4 g)was recrystallized form ethanol and then triturated with diethyl etherto provide 0.9 g of2-methyl-1-[2-(methylthio)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine as afine white powder, m.p. 193-195° C.

[0413] Analysis: Calculated for C₁₄H₁₆N₄S: % C, 61.74; % H, 5.92; % N,20.57; Found: % C, 61.64; % H, 5.97; % N, 20.66. ¹H NMR (300 MHz,DMSO-d6) δ 8.00 (dd, J=7.8, 1.5 Hz, 1 H), 7.61 (dd, J=8.1, 1.4 Hz, 1 H),7.19 (dt, J=7.8, 1.2 Hz, 1 H), 7.25 (dt, J=7.5, 1.5 Hz, 1 H), 6.51 (s, 2H), 4.72 (t, J=6.9 Hz, 2 H), 2.99 (t, J=6.8 Hz, 2 H), 2.66 (s, 3 H),2.08 (s, 3 H); MS(CI) m/e 273 (M+H).

EXAMPLE 332-methyl-1-[2-(methylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0414]

[0415] 3-Chloroperbenzoic acid (3.35 g of 75%, 14:54 mmol) was added inportions to a suspension of2-methyl-1-[2-(methylthio)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.8g, 6.61 mmol) in chloroform (33 mL). After about 1 equivalent of theoxidant had been added, a precipitate formed. Additional chloroform wasadded along with the remaining oxidant. The reaction mixture was stirredat ambient temperature for 1 hour and then it was chilled in an icebath. A white solid was isolated by filtration and then washed with colddichloromethane. This solid was suspended in water (100 mL). Solidsodium carbonate was added until the pH reached 10. The suspension wasstirred at ambient temperature for several hours then the solid wasisolated by filtration and washed with water to provide ˜1.5 g of anoff-white solid. Analysis by H-NMR indicated that sulfoxide was present.This material was suspended in dichloromethane (23 mL) and3-chloroperbenzoic acid (0.25 g) was added in portions. After about 15minutes another portion of oxidant was added. The reaction mixture wasconcentrated under reduced pressure. The residue was stirred in water(100 mL) and solid sodium carbonate was added until the pH reached 10. Abrown solid was isolated by filtration and washed with water. Thismaterial was purified by chromatography (silica gel eluting with 95/5dichloromethane/methanol) to provide a white solid. This material wastriturated with diethyl ether to provide 0.56 g of2-methyl-1-[2-(methylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinolin-4-amineas a fine white powder, m.p. 242-245° C.

[0416] Analysis: Calculated for C₁₄H₁₆N₄O₂S: % C, 55.25; % H, 5.30; % N,18.41; Found: % C, 54.92; % H, 5.19; % N, 18.29. ¹H NMR (300 MHz,DMSO-d₆) δ 8.05 (d, J=6.6 Hz, 1 H), 7.63 (d, J=6.6 Hz, 1 H), 7.43 (t,J=7.2 Hz, 1 H), 7.25 (t, J=6.9, Hz, 1 H), 6.31 (s, 2 H), 4.95 (t, J=7.2Hz, 2 H), 3.77 (t, J=7.2 Hz, 2 H), 3.08 (s, 3 H), 2.66 (s, 3 H); MS(CI)m/e 305 (M+H).

EXAMPLE 342-methyl-1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0417]

Part A

[0418] Sodium thiomethoxide (2.02 g of 95%, 27.40 mmol) was added in asingle portion to a solution of1-(4-chlorobutyl)-2-methyl-1H-imidazo[4,5-c]quinoline (5.0 g, 18.26mmol) in anhydrous N,N-dimethylformamide (91 mL). After 30 minutes thereaction mixture was poured with rapid stirring into water (500 mL). Theresulting solution was extracted with chloroform (2×200 mL). The organiclayers were combined, washed with saturated aqueous sodium bicarbonate(100 mL) then with brine (100 mL), dried over sodium sulfate, filteredand then concentrated under reduced pressure to provide 5.0 g2-methyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinoline as a lightyellow oil.

Part B

[0419] Using the general method of Example 11 Part F, the material fromPart A was oxidized to provide2-methyl-1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinoline-5N-oxideas a light orange solid.

Part C

[0420] Using the general method of Example 3 Part B except thatdichloromethane was used as a solvent in place of chloroform, thematerial from Part B was aminated. The crude material was purified bychromatography (silica gel eluting with 90/10 dichloromethane/methanol)followed by trituration with diethyl ether to provide 1.67 g of2-methyl-1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amineas a fine white solid, m.p. 206-209° C.

[0421] Analysis: Calculated for C₁₆H₂₀N₄O₂S: % C, 57.81; % H, 6.06; % N,16.85; Found: % C, 57.70; % H, 6.10; % N, 16.64. ¹H NMR (300 MHz,DMSO-d₆) δ 8.05 (d, J=8.1 Hz, 1 H), 7.61 (d, J=8.7 Hz, 1 H), 7.42 (t,J=7.8 Hz, 1 H), 7.25 (t, J=7.6 Hz, 1 H), 6.51 (s, 2 H), 4.55 (t, J=7.2Hz, 2 H), 3.20 (t, J=7.4Hz, 2 H), 2.96 (s, 3 H), 2.61 (s, 3 H), 1.91 (m,4 H); MS(CI) m/e 333 (M+H).

EXAMPLE 352-ethyl-1-[2-(methylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0422]

Part A

[0423] Using the general method of Example 1 Part A,4-chloro-3-nitroquinoline (15.0 g, 71.90 mol) was reacted with2-chloroethylamine monohydrochloride (8.3 g, 71.90 mmol). The crudeproduct was suspended in water (300 mL) and solid sodium carbonate wasadded to adjust the pH to 10. The suspension was stirred overnight andthen cooled in an ice bath. The solid was then isolated by filtrationand washed with chilled water to provide 15.88 g ofN-(2-chloroethyl)-3-nitroquinolin-4-amine as a bright yellow fluffysolid.

Part B

[0424] Using the general method of Example 21 Part D,N-(2-chloroethyl)-3-nitroquinolin-4-amine (6.0 g, 23.84 mmol) wasreacted with sodium thiomethoxide (2.11 g of 95%, 28.61 mmol) to provide4.95 g of N-[2-(methylthio)ethyl]-3-nitroquinolin-4-amine as a dullyellow solid.

Part C

[0425] Using the general method of Example 1 Part C,N-[2-(methylthio)ethyl]-3-nitroquinolin-4-amine (4.71 g, 17.89 mmol) wasreduced to provide N⁴-[2-(methylthio)ethyl]quinoline-3,4-diamine as alight brown oil.

Part D

[0426] Using the general method of Example I Part D, the material fromPart C was cyclized using triethyl orthopropionate. The crude productwas purified by chromatography (silica gel eluting with 95/5dichloromethane/methanol) to provide 3.1 g of2-ethyl-1-[2-(methylthio)ethyl]-1H-imidazo[4,5-c]quinoline as anoff-white solid.

Part E

[0427] Using the general method of Example 11 Part F, the material fromPart D was oxidized to provide 3.3 g of2-ethyl-1-[2-(methylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinoline-5N-oxideas an off-white solid.

Part F

[0428] Using the general method of Example 3 Part B, the material fromPart E was aminated and purified to provide 0.2 g of2-ethyl-1-[2-(methylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine asa solid, m.p. 222-225° C.

[0429] Analysis: Calculated for C₁₅H₁₈N₄O₂S: % C, 56.59; % H 5.70; % N,17.60; Found: % C, 56.37; % H, 5.59; % N, 17.34. ¹H NMR (300 MHz,DMSO-d₆) δ 8.06 (d, J=8.7 Hz, 1 H), 7.63 (d, J=8.7 Hz, 1 H), 7.44 (t,J=8.1, Hz, 1 H), 7.26 (t, J=8.1, Hz, 1 H), 6.50 (s, 2 H), 4.95 (t,J=7.2Hz, 2 H), 3.78 (t, J=7.2 Hz, 2 H), 3.12 (s, 3 H), 3.02 (quartet,J=7.5 Hz, 2 H), 1.39 (t, J=7.2 Hz, 3 H); MS(CI) m/e 319 (M+H).

EXAMPLE 361-[2-(methylsulfonyl)ethyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine

[0430]

Part A

[0431] N⁴-[2-(Methylthio)ethyl]quinoline-3,4-diamine (4.2 g, 19.2 mmol),trimethyl orthobutyrate (2.86 g, 19.2 mmol), pyridine hydrochloride(catalytic amount) and toluene were combined in a pressure vessel andheated at 140° C. for 1 hour. The reaction mixture was allowed to cooland then it was concentrated under reduced pressure to provide 4.9 g of1-[2-(methylthio)ethyl]-2-propyl-1H-imidazo[4,5-c]quinoline.

Part B

[0432] 3-Chloroperbenzoic acid (14.12 g of 65%, 53.2 mmol) was added inportions to a solution of the material from Part A in chloroform (100mL). After about 30 minutes the reaction mixture was washed with aqueoussodium carbonate, water and then with brine. The organic layer wascombined with excess ammonium hydroxide. p-Toluenesulfonyl chloride (3.6g, 18.9 mmol) was added in portions accompanied by vigorous stirring.After 1 hour the reaction mixture was diluted with chloroform (100 mL)and water (100 mL). The organic layer was separated, washed with waterand then concentrated under reduced pressure. The resulting oil waspurified by chromatography (silica gel eluting with 98/2dichloromethane/methanol). The material crystallized fromdichloromethane and was isolated by filtration to provide 0.9 g of1-[2-(methylsulfonyl)ethyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amineas a solid, m.p. 212-214° C.

[0433] Analysis: Calculated for C₁₆H₂N₄O₂S.0.08 CH₂Cl₂: % C, 56.94; % H,5.99; % N, 16.52 Found: % C, 56.95; % H, 5.91; % N, 16.59. ¹H NMR (300MHz, DMSO-d₆) δ 8.06 (d, J=7.5 Hz, 1 H), 7.64 (d, J=7.2 Hz, 1 H), 7.43(t, J=7.2 Hz, 1 H), 7.25 (t, J=6.9 Hz, 1 H), 6.47 (s, 2 H), 4.94 (t,J=7.2 Hz, 2 H), 3.76 (t, J=7.2 Hz, 2 H), 3.11 (s, 3 H), 2.97 (t, J=7.5Hz, 2 H), 1.87 (sextet, J=7.2 Hz, 2 H), 1.04 (t, J=7.2Hz, 3 H); MS (CI)m/e 333 (M+H).

EXAMPLE 37 2-butyl-1-{4-[(2,4-difluorophenyl)thio]butyl}-1H-imidazo[4,5-c]quinolin-4-amine

[0434]

Part A

[0435] Using the general method of Example 1 Part D,N⁴-(4-chlorobutyl)quinoline-3,4-diamine (119.1 g, 0.48 mole) wascyclized using trimethyl orthovalerate (93 g, 0.57 mol) in the presenceof pyridine hydrochloride (1.1 g, 0.0095 mol) to provide 120 g of2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinoline as an ivory powder.

Part B

[0436] 3-Chloroperbenzoic acid (110 g of 77%, 0.45 mol) was added inportions over a period of 30 minutes to a solution of2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinoline (118 g, 0.037 mol)in dichloromethane (1700 mL). After about 90 minutes the reactionmixture was diluted with additional dichloromethane, washed with 10%sodium hydroxide (×3) and brine, and then dried to provide2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinoline-5N-oxide.

Part C

[0437] Concentrated ammonium hydroxide (1100 mL) was added to thedichloromethane solution of2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinoline-5N-oxide from PartB. Tosyl chloride (68 g, 0.36 mol) was added in portions accompanied byvigorous stirring. After 30 minutes the layers were separated. Theorganic layer was diluted with dichloromethane, washed with 10% sodiumhydroxide (×2) and brine, dried and then concentrated under reducedpressure to provide a tan solid. This material was recrystallized fromacetonitrile (30 mL/g) to provide 91.6 g of2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinoline-4-amine as tanneedles.

[0438] Analysis: Calculated for C₁₈H₂₃ClN₄: % C, 65.34; % H, 7.01; % N,16.93; Found: % C, 65.32; % H, 7.09; % N, 16.94.

Part D

[0439] 2,4-Difluorobenzenethiol (2 g, 13.7 mmol) was added to asuspension of sodium hydride (0.65 g of 60%, 16.5 mmol) in anhydrousN,N-dimethylformamide (30 mL). After the addition was complete thereaction mixture was allowed to stir at ambient temperature for about 30minutes. 2-Butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinoline-4-amine(4.5 g, 13.6 mmol) was added in a single portion. The reaction mixturewas allowed to stir at ambient temperature for about 30 minutes; then itwas poured into ice water and stirred. The aqueous layer was extractedwith dichloromethane (5×75 mL). The combined organics were washed withwater (3×100 mL) and brine, and then concentrated under reduced pressureto provide 6.7 g of a solid. This material was recrystallized fromethanol. A portion (1.1 g) was dried in a heated vacuum oven to provide2-butyl-1-{4-[(2,4-difluorophenyl)thio]butyl }-1H-imidazo[4,5-c]quinolinas a solid, m.p. 122-126° C.

[0440] Analysis: Calculated for C₂₄H₂₆F₂N₄S: % C, 65.43; % H, 5.95; % N,12.72; Found: % C, 65.41; % H, 5.98; % N, 12.80. ¹H NMR (300 MHz,DMSO-d₆) δ 8.02 (d, J=7.5 Hz, 1 H), 7.62 (d, J=7.2 Hz, 1 H), 7.42 (m, 2H), 7.25 (m, 2 H), 7.05 (t, J=6 Hz, 1 H), 6.46 (s, 2 H), 4.50 (t, J=7.5Hz, 2 H), 2.97 (t, J=6.6 Hz, 2 H), 2.87 (t, J=7.2 Hz, 2 H), 1.92(quintet, J=7.8 Hz, 2 H), 1.76 (quintet, J=7.8 Hz, 2 H), 1.64 (quintet,J=7.5 Hz, 2 H), 1.42 (sextet, J=7.5 Hz, 2 H), 0.94 (t, J=7.2 Hz, 3 H);MS (CI) m/e 441 (M+H).

EXAMPLE 382-butyl-1-{4-[(2,4-difluorophenyl)sulfonyl]butyl}-1H-imidazo[4,5-c]quinolin-4-amine

[0441]

[0442] 3-Chloroperbenzoic acid (6.025 g of 65%, 22.6 mmol) was added inportions to a solution of2-butyl-1-{4-[(2,4-difluorophenyl)thio]butyl}-1H-imidazo[4,5-c]quinolin-4-amine(5.0 g, 11.3 mmol) in dichloromethane (50 mL). After the addition wascompleted the reaction mixture was allowed to stir for about 30 minutes.The reaction mixture was partitioned between dichloromethane and aqueoussodium carbonate. The aqueous layer was extracted with dichloromethane(3×500 mL). The combined organics were washed with water (5×100 mL) andbrine and then concentrated under reduced pressure. The residue (6.1 g)was recrystallized from ethanol to provide2-butyl-1-{4-[(2,4-difluorophenyl)sulfonyl]butyl}-1H-imidazo[4,5-c]quinolin-4-amineas a solid, m.p. 190-193° C.

[0443] Analysis: Calculated for C₂₄H₂₆F₂N₄O₂S: % C, 61.00; % H, 5.55; %N, 11.86; Found: % C, 61.33; % H, 5.38; % N, 11.70. ¹H NMR (300 MHz,DMSO-d₆) δ 8.00 (d, J=8.1 Hz, 1 H), 7.83 (q, J=8.7 Hz, 1 H), 7.62 (m, 2H), 7.41 (m, 2 H), 7.22 (t, J=6.9 Hz, 1 H), 6.46 (s, 2 H), 4.51 (t,J=6.9 Hz, 2 H), 3.49 (t, J=7.5 Hz, 2H), 2.87 (t, J=7.5 Hz,2 H), 1.90(m,2 H), 1.77 (m,4H), 1.43 (sextet, J=7.5 Hz, 2 H), 0.95 (t, J=7.5 Hz, 3H); MS (CI) m/e 473 (M+H).

EXAMPLES 39-42

[0444] The thioethers shown in the table below were prepared by reacting2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinoline-4-amine with theappropriate thiol using the method of Example 37 Part D. The sulfoneswere prepared by oxidizing the appropriate thioether using the method ofExample 38.

Example Z R₁ m.p. (° C.) Elemental Analysis 39 SO₂ ethyl 141-143 Calc'dfor C₂₀H₂₈N₄O₂S · 0.18 EtOH % C, 61.63; % H, 7.39; % N, 14.12 Fd: % C,61.73; % H, 7.14; % N, 14.48 40 S 1,1-dimethylethyl 185-187 Calc'd forC₂₂H₃₂N₄S % C, 68.71; % H, 8.39; % N, 14.57 Fd: % C, 68.82; % H, 8.31; %N, 14.76 41 S 4-fluorophenyl 122-125 Calc'd for C₂₄H₂₇FN₄S · 0.5 EtOH %C, 68.22; % H, 6.44; % N 13.26 Fd: % C, 68.32; % H, 6.53; % N, 13.32 42SO₂ 4-fluorophenyl 173-174 Calc'd for C₂₄H₂₇FN₄O₂S · 0.04 EtOH % C,63.37; % H, 6.02; % N 12.28 Fd: % C, 63.58; % H, 5.95; % N, 12.68

[0445] NMR and mass spectroscopy data are given in the table below.Example Mass Spectroscopy NMR 39 MS(CI) m/e 389 ¹H NMR(300MHz, DMSO-d₆)δ 8.05(d, J=8.1Hz, 1 (M + H) H), 7.62(d, J=6.9Hz, 1H), 7.42(t, J=8.1Hz,1H), 7.25(t, J=6.9Hz, 1H), 6.46(s, 2H), 4.56(t, J=7.5Hz, 2H), 3.17(t,J=7.5Hz, 2H), 3.07(q, J=7.5Hz, 2 H), 2.93(t, J=7.5Hz, 2H), 1.85(m, 6H),1.46(sextet, J=7.5Hz, 2H), 1.20(t, J=7.5Hz, 3H), 0.96(t, J=7.5Hz, 3H);40 MS(CI) m/e 385 ¹H NMR(300MHz, DMSO-d₆) δ 8.05(d, J=7.2Hz, 1 (M + H)H), 7.61(d, J=7.5Hz, 1H), 7.41(t, J=6.6Hz, 1H), 7.24(t, J=6.9Hz, 1H),6.44(s, 2H), 4.51(t, J=7.5Hz, 2H), 2.92(t, J=7.5Hz, 2H), 2.57(t,J=6.6Hz, 2 H), 1.90(m, 2H), 1.80(m, 2H), 1.65(quintet, J=8.4Hz, 2H),1.45(sextet, J=7.5Hz, 2H), 1.24(s, 9H), 0.96(t, J=6.6Hz, 3H); 41 MS(CI)m/e 423 ¹H NMR(300MHz, DMSO-d₆) δ 8.02(d, J=7.5Hz, 1 (M + H) H), 7.62(d,J=6.9Hz, 1H), 7.41(t, J=7.2Hz, 1H), 7.31(m, 2H), 7.22(t, J=6.6Hz, 1H),7.13(m, 2H), 6.44(s, 2H), 4.51(t, J=7.5Hz, 2H), 2.98(t, J=6.6Hz, 2H),2.87(t, J=7.5Hz, 2H), 1.92(quintet, J=6.6Hz, 2H), 1.72(m, 4H),1.42(sextet, J=7.2Hz, 2H), 0.94(t, J=6.9Hz, 3H); 42 MS(CI) m/e 455 ¹HNMR(300MHz, DMSO-d₆) δ 8.00(d, J=8.1Hz, 1 (M + H) H), 7.88(m, 2H),7.61(m, 1H), 7.46(m, 3H), 7.22(t, J=6.9Hz, 1H), 6.45(s, 2H), 4.51(t,J=6.9Hz, 2H), 3.41(t, J=7.8Hz, 2H), 2.86(t, J=7.2Hz, 2H), 1.77 (m, 6H),1.43(sextet, J=8.1Hz, 2H), 0.94(t, J=7.5Hz, 3H);

EXAMPLES 43-55 Part A

[0446] Using the general method of Example 1 Part D,N⁴-(4-chlorobutyl)quinoline-3,4-diamine (30 g, 0.12 mole) was cyclizedusing trimethyl orthopropionate (23.3 g, 0.13 mol) in the presence of acatalytic amount of pyridine hydrochloride to provide 25.1 g of1-(4-chlorobutyl)-2-ethyl-1H-imidazo[4,5-c]quinoline as solid.

Part B

[0447] 3-Chloroperbenzoic acid (20.1 g of 60%, 0.117 mole) was added inportions to a solution of1-(4-chlorobutyl)-2-ethyl-1H-imidazo[4,5-c]quinoline (24 g, 0.084 mol)in dichloromethane. The reaction mixture was diluted with enough 5%sodium carbonate to maintain the aqueous layer at pH 9-10. The layerswere separated. The organic layer was washed sequentially withadditional sodium carbonate, water (250 mL) and brine and thenconcentrated under reduced pressure. The resulting residue was dissolvedin chloroform (350 mL). Ammonium hydroxide (250 mL) was added withvigorous stirring to form an emulsion. Tosyl chloride (19.2 g, 0.10 mol)was added in portions with stirring. The reaction mixture was washedwith water (2×100 mL), 5% sodium carbonate (2×200 mL), and brine; driedover sodium carbonate and then concentrated under reduced pressure. Theresidue was combined with diethyl ether and stirred overnight. Theresulting solid was isolated by filtration and air dried to provide 19.3g of 1-(4-chlorobutyl)-2-ethyl-1H-imidazo[4,5-c]quinoline-4-amine.

Part C

[0448] The thioethers shown in the table below were prepared by reacting1-(4-chlorobutyl)-2-ethyl-1H-imidazo[4,5-c]quinoline-4-amine with theappropriate thiol using the method of Example 37 Part D. The sulfoneswere prepared by oxidizing the appropriate thioether using the method ofExample 38.

Example Z R₁ m.p. (° C.) Elemental Analysis 43 S 1-methylethyl 138-142Calc'd for: C₁₉H₂₆N₄S % C, 66.63; % H, 7.65; % N, 16.36 Fd: % C, 66.92;% H, 7.64; % N, 16.46 44 S 3,5-dichlorophenyl 172-175 Calc'd for:C₂₂H₂₂Cl₂N₄S: % C, 59.33; % H, 4.98: % N, 12.58 Fd: % C, 59.21; % H,4.97; % N, 12.56 45 SO₂ cyclopentyl 163 (dec.) Calc'd for: C₂₁H₂₈N₄O₂S %C, 62.97; % H, 7.05; % N, 13.99 Fd: % C, 62.83; % H, 6.91; % N, 14.02 46SO₂ 3,5-dichlorophenyl 199-202 Calc'd for: C₂₂H₂₂Cl₂N₄O₂S · 0.04 EtOH %C, 55.34; % H, 4.68: % N, 11.69 Fd: % C, 55.44; % H, 4.81; % N,~11.74 47S cyclohexyl 139-143 Calc'd for: C₂₂H₃₀N₄S % C, 69.07; % H, 7.90; % N,14.64 Fd: % C, 68.88; % H, 7.83; % N, 14.42 48 S butyl 122 (dec.) Calc'dfor: C₂₀H₂₈N₄S · 0.40 H₂O % C, 66.04; % H, 7.98; % N, 15.40 Fd: % C,66.10; % H, 7.91; % N, 15.16 49 S 4-chlorophenyl 163-166 Calc'd for:C₂₂H₂₃ClN₄S · 0.25 EtOH % C, 63.97; % H, 5.85; % N, 13.26 Fd: % C,63.75; % H, 5.70; % N, 13.29 50 SO₂ butyl 164-168 Calc'd for:C₂₀H₂₈N₄O₂S · 0.05 CH₂Cl₂ % C, 61.31; % H, 7.21; % N, 14.26 Fd: % C,61.34; % H, 7.25; % N, 14.01 51 S 4-fluorophenyl 156 (dec.) Calc'd for:C₂₂H₂₃FN₄S % C, 66.98; % H, 5.88; % N, 14.20 Fd: % C, 66.61; % H, 5.84;% N, 14.17 52 SO₂ 1-methylethyl 200-202 Calc'd for: C₁₉H₂₆N₄O₂S · 0.21CH₃CN % C, 60.88; % H, 7.01; % N, 15.39 Fd: % C, 60.61; % H, 7.24; % N,15.04 53 S ethyl 141-143 Calc'd for: C₁₈H₂₄N₄S % C, 65.82; % H, 7.36; %N, 17.06 Fd: % C, 65.54; % H, 7.22; % N, 16.86 54 SO₂ ethyl 170-174Calc'd for: C₁₈H₂₄N₄O₂S · 0.21 CH₃CN % C, 59.94; % H, 6.73; % N, 15.98Fd: % C, 59.93; % H, 6.87; % N, 15.71 55 SO₂ cyclohexyl 203-205 Calc'dfor: C₂₂H₃₀N₄O₂S % C, 63.74; % H, 7.29; % N, 13.51 Fd: % C, 63.42; % H,7.25; % N, 13.86

[0449] NMR and mass spectroscopy data are shown in the table below. MassExample Spectroscopy NMR 43 MS(CI) m/e 343 ¹H NMR(300MHz, DMSO-d₆) δ8.05(d, J=8.1Hz, 1 (M + H) H), 7.61(d, J=6.6Hz, 1H), 7.41(t, J=7.8Hz,1H), 7.24(t, J=6.9Hz, 1H), 6.45(s, 2H), 4.51(t, J=7.5Hz, 2H), 2.93(m,3H), 2.56(t, J=7.8Hz, 2H), 1.89 (quintet, J=8.4Hz, 2H), 1.66(quintet,J=7.5Hz, 2H), 1.37(t, J=7.5Hz, 3H), 1.16(d, 6H, J=6.7Hz); 44 MS(CI) m/e445 ¹H NMR(300MHz, DMSO-d₆) δ 8.02(d, J=7.2Hz, 1 (M + H) H), 7.63(d,J=7.8Hz, 1H), 7.40(t, J=6.9Hz, 1H), 7.34(t, J=1.8Hz, 1H), 7.32(d,J=1.8Hz, 2H), 7.21(t, J=7.2Hz, 1H), 6.26(s, 2H), 4.51(t, J=7.5Hz, 2H),3.12(t, J=7.2Hz, 2H), 2.92(q, J=7.2Hz, 2H), 1.94 (quintet, J=8.4Hz, 2H),1.75(quintet, J=7.2Hz, 2H), 1.37(t, J=7.5Hz, 3H); 45 MS(CI) m/e 401 ¹HNMR(300MHz, DMSO-d₆) δ 8.06(d, J=7.2Hz, 1 (M + H) H), 7.62(d, J=7.2Hz,1H), 7.41(t, J=6.9Hz, 1H), 7.25(t, J=6.9Hz, 1H), 6.48(s, 2H), 4.55(t,J=6.6Hz, 2H), 3.51(quintet, J=8.4Hz, 1H), 3.13(t, J=7.8Hz, 2 H), 2.96(q,J=7.5Hz, 2H), 1.87(m, 8H), 1.61(m, 4 H), 1.37(t, J=7.5Hz, 3H); 46 MS(CI)m/e 477 ¹H NMR(300MHz, DMSO-d₆) δ 8.08(t, J=1.8Hz, 1 (M + H) H), 8.01(d,J=7.2Hz, 1H), 7.89(d, J=1.8Hz, 2H), 7.61(dd, J=8.4; 1.2Hz, 1H), 7.41(t,J=7.2Hz, 1H), 7.22(t, J=7.2Hz, 1H), 6.45(s, 2H), 4.52(t, J=6.9Hz, 2H),3.57(t, J=7.5Hz, 2H), 2.90(q, J=7.5Hz, 2H), 1.88(m, 2H), 1.73(m, 2H),1.35(t, J=6.9Hz, 3H); 47 MS(CI) m/e 383 ¹H NMR(300MHz, DMSO-d₆) δ8.06(d, J=7.5Hz, 1 (M + H) H), 7.62(d, J=6.9Hz, 1H), 7.41(t, J=6.9Hz,1H), 7.23(t, J=6.9Hz, 1H), 6.46(s, 2H), 4.51(t, J=7.2Hz, 2H), 2.94(q,J=7.5Hz, 2H), 2.55(m, 2H), 1.84(m, 4 H), 1.66(m, 5H), 1.37(t, J=6.9Hz,3H), 1.19(m, 6H); 48 MS(CI) m/e 357 ¹H NMR(300MHz, DMSO-d₆) δ 8.05(d,J=6.9Hz, 1 (M + H) H), 7.62(d, J=6.6Hz, 1H), 7.41(t, J=6.9Hz, 1H),7.24(t, J=7.5Hz, 1H), 6.46(s, 2H), 4.51(t, J=7.2Hz, 2H), 2.95(q,J=7.2Hz, 2H), 2.56(m, 2H), 2.44(t, J=6.6Hz, 2H), 1.89(quintet, J=7.5Hz,2H), 1.66 (quintet, J=7.5Hz, 2H), 1.37(m, 7H), 0.84(t, J=7.8Hz, 3H); 49MS(CI) m/e 411 ¹H NMR(300MHz, DMSO-d₆) δ 8.02(d, J=7.5Hz, 1 (M + H) H),7.63(d, J=7.2Hz, 1H), 7.41(t, J=7.5Hz, 1H), 7.31(m, 4H), 7.22(t,J=6.9Hz, 1H), 6.48(s, 2H), 4.50 (t, J=7.5Hz, 2H), 3.02(t, J=6.9Hz, 2H),2.91(q, J=7.5Hz, 2H), 1.93(quintet, J=6.9Hz, 2H), 1.69 (quintet,J=7.8Hz, 2H), 1.35(t, J=7.5Hz, 3H); 50 MS(CI) m/e 389 ¹H NMR(300MHz,DMSO-d₆) δ 8.06(d, J=7.8Hz, 1 (M + H) H), 7.62(d, J=7.8Hz, 1H), 7.41(t,J=7.8Hz, 1H), 7.25(t, J=6.9Hz, 1H), 6.48(s, 2H), 4.55(t, J=6.9Hz, 2H),3.16(t, J=8.1Hz, 2H), 3.05(m, 2H), 2.96(q, J=7.5Hz, 2H), 1.89(m, 4H),1.63(m, 2H), 1.42(m, 2H), 1.35(t, J=7.5Hz, 3H), 0.88(t, J=7.5Hz, 3H); 51MS(CI) m/e 395 ¹H NMR(300MHz, DMSO-d₆) δ 8.02(d, J=7.5Hz, 1 (M + H) H),7.63(d, J=6.9Hz, 1H), 7.42(t, J=6.9Hz, 1H), 7.31(m, 2H), 7.22(t,J=6.6Hz, 1H), 7.13(m, 2H), 6.49(s, 2H), 4.50(t, J=7.5Hz, 2H), 2.98(t,J=6.9Hz, 2H), 2.91(q, J=7.5Hz, 2H), 1.92(quintet, J=7.5Hz, 2 H),1.65(quintet, J=8.1Hz, 2H), 1.35(t, J=7.5Hz, 3 H); 52 MS(CI) m/e 375 ¹HNMR(300MHz, DMSO-d₆) δ 8.06(d, J=8.1Hz, 1 (M + H) H), 7.63(d, J=7.5Hz,1H), 7.42(t, J=6.9Hz, 1H), 7.23(t, J=6.9Hz, 1H), 6.51(s, 2H), 4.56(t,J=6.6Hz, 2H), 3.22(q, J=6.9Hz, 1H), 3.14(t, J=6.9Hz, 2H), 2.96(q,J=7.5Hz, 2H), 1.90(m, 4H), 1.38(t, J=7.5Hz, 3H), 1.22(d, 6H, J=6.9Hz);53 MS(CI) m/e 329 ¹H NMR(300MHz, DMSO-d₆) δ 8.05(d, J=8.1Hz, 1 (M + H)H), 7.62(d, J=6.9Hz, 1H), 7.41(t, J=7.5Hz, 1H), 7.24(t, J=6.9Hz, 1H),6.48(s, 2H), 4.51(t, J=7.5Hz, 2H), 2.94(q, J=7.5Hz, 2H), 2.55(t, J7.2Hz, 2H), 2.47(q, J=7.5Hz, 2H), 1.89(quintet, J=8.1Hz, 2H),1.67(quintet, J=7.5Hz, 2H), 1.37(t, J=7.5Hz, 3H), 1.14(t, J=7.5Hz, 3H);54 MS(CI) m/e 361 ¹H NMR(300MHz, DMSO-d₆) δ 8.05(d, J=8.1Hz, 1 (M + H)H), 7.62(d, J=7.5Hz, 1H), 7.41(t, J=6.6Hz, 1H), 7.25(t, J=7.5Hz, 1H),6.48(s, 2H), 4.55(t, J=6.9Hz, 2H), 3.16(t, J=7.8Hz, 2H), 3.06(q,J=7.2Hz, 2H), 2.96(q, J=6.9Hz, 2H), 1.90(m, 4H), 1.38(t, J=7.5Hz, 3H),1.20(t, J=7.5Hz, 3H); 55 MS(CI) m/e 415 ¹H NMR(300MHz, DMSO-d₆) δ8.06(d, J=7.5Hz, 1 (M + H) H), 7.62(d, J=7.2Hz, 1H), 7.41(t, J=6.9Hz,1H), 7.25(t, J=6.9Hz, 1H), 6.46(s, 2H), 4.55(t, J=6.6Hz, 2H), 3.11(t,J=7.8Hz, 2H), 2.97(m, 3H), 1.99(m, 8 H), 1.64(d, J=11.7Hz, 1H), 1.37(t,J=7.5Hz, 4H), 1.27(m, 4H);

EXAMPLES 56-66 Part A

[0450] Thionyl chloride (3.8 g, 32 mmol) was added to a solution of2-butyl-1-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.7 g, 13mmol) in toluene containing a catalytic amount of N,N-dimethylformamide.The reaction mixture was heated to reflux and then capped. When analysisby high performance liquid chromatography indicated that the reactionwas complete, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in warm methanol and then combinedwith concentrated ammonium hydroxide (5 mL). The mixture was chilled.The resulting precipitate was isolated by filtration, washed with coldmethanol and then dried under vacuum overnight to provide 3.01 g of2-butyl-1-(2-chloroethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a brownsolid.

Part B

[0451] The thioethers shown in the table below were prepared by reacting2-butyl-1-(2-chloroethyl)-1H-imidazo[4,5-c]quinoline-4-amine with theappropriate thiol using the method of Example 37 Part D. The sulfoneswere prepared by oxidizing the appropriate thioether using the method ofExample 38.

Example Z R₁ m.p. (° C.) Elemental Analysis 56 SO₂ 1-methylethyl 177-179Calc'd for: C₁₉H₂₆N₄O₂S · 1.0 EtOH % C, 60.94; % H, 7.00; % N, 14.96 Fd:% C, 60.97; % H, 6.93; % N, 15.11 57 SO₂ phenyl 223-225 Calc'd for:C₂₂H₂₄N₄O₂S % C, 64.68; % H, 5.92; % N, 13.71 Fd: % C, 64.65; % H, 5.91;% N, 13.72 58 SO₂ 4-fluorophenyl 244-247 Calc'd for: C₂₂H₂₃FN₄O₂S % C,61.95; % H, 5.44; % N, 13.14 Fd: % C, 61.94; % H, 5.34; % N, 13.16 59 S1,1-dimethylethyl 159-160 Calc'd for: C₂₀H₂₈N₄S % C, 67.38; % H, 7.92; %N, 15.71 Fd: % C, 67.25; % H, 7.83; % N, 15.73 60 SO₂ 1,1-dimethylethyl201 (dec) Calc'd for: C₂₀H₂₈N₄O₂S · 0.20 EtOH % C, 61.60; % H, 7.40; %N, 14.09 Fd: % C, 61.86; % H, 7.34; % N, 14.16 61 S propyl 117-119Calc'd for: C₁₉H₂₆N₄₅ % C, 66.63; % H, 7.65; % N, 16.36 Fd: % C, 66.69;% H, 7.56; % N, 16.47 62 SO₂ propyl 168-171 Calc'd for: C₁₉H₂₆N₄O₂S % C,60.94; % H, 7.00; % N, 14.96 Fd: % C, 60.91; % H, 7.04; % N, 14.87 63 S2-methylpropyl 128-130 Calc'd for: C₂₀H₂₈N₄S % C, 67.38; % H, 7.92; % N,15.71 Fd: % C, 67.58; % H, 7.75; % N, 15.84 64 SO₂ 2-methylpropyl170-171 Calc'd for: C₂₀H₂₈N₄O₂S % C, 61.83; % H, 7.26; % N, 14.42 Fd: %C, 61.92; % H, 7.19; % N, 14.53 65 S ethyl 80-82 Calc'd for: C₁₈H₂₄N₄S %C, 65.82; % H, 7.36; % N, 17.06 Fd: % C, 65.67; % H, 7.07; % N, 17.03 66SO₂ ethyl 167-170 Calc'd for: C₁₈H₂₄N₄O₂S % C, 59.98; % H, 6.71; % N,15.54 Fd: % C, 60.24; % H, 6.62; % N, 15.75

[0452] NMR and mass spectroscopy data are given in the table below.Example Mass Spectroscopy NMR 56 MS(CI) m/e 375 ¹H NMR(300MHz, DMSO-d₆)δ 8.06(d, J=8.1Hz, 1 (M + H) H), 7.64(d, J=8.1Hz, 1H), 7.43(t, J=6.9Hz,1H), 7.25(t, J=6.9Hz, 1H), 6.49(s, 2H), 4.95(t, J=6.9Hz, 2H), 3.70(t,J=7.5Hz, 2H), 3.38(septet, J=6.9, 1H), 3.00(t, J=7.8Hz, 2H),1.82(quintet, J=8.1Hz, 2H), 1.47(sextet, J=7.5Hz, 2H), 1.25(d, 6H,J=6.9Hz), 0.98(t, J=7.5Hz, 3H); 57 MS(CI) m/e 409 ¹H NMR(300MHz,DMSO-d₆) δ 7.99(d, J=7.8Hz, 2 (M + H) H), 7.83(t, J=7.5Hz, 1H), 7.71(t,J=7.5Hz, 2H), 7.59(d, J=9Hz, 2H), 7.38(t, J=7.5Hz, 1H), 7.05(t, J=6.9Hz,1H), 6.46(s, 2H), 4.78(t, J=6.9Hz, 2H), 3.96(t, J=8.1Hz, 2H), 2.86(t,J=7.5Hz, 2H), 1.74 (quintet, J=7.5Hz, 2H), 1.41(sextet, J=7.5Hz, 2H),0.94(t, J=6.9Hz, 3H); 58 MS(CI) m/e 427 ¹H NMR(300MHz, DMSO-d₆) δ8.02(m, 2H), 7.66 (M + H) (d, J=6.9Hz, 1H), 7.57(m, 3H), 7.4(t, J=7.5Hz,1 H), 7.09(t, J=6.9Hz, 1H), 6.45(s, 2H), 4.80(t, J=7.8Hz, 2H), 3.99(t,J=6.9Hz, 2H), 2.87(t, J=8.1Hz, 2H), 1.75(quintet, J=7.5Hz, 2H),1.39(sextet, J=7.5Hz, 2H), 0.94(t, J=7.5Hz, 3H); 59 MS(CI) m/e 357 ¹HNMR(300MHz, DMSO-d₆) δ 8.19(d, J=9Hz, 1 (M + H) H), 7.82(d, J=7.5Hz,1H), 7.62(t, J=6.9Hz, 1H), 7.45(t, J=6.9Hz, 1H), 6.69(s, 2H), 4.85(t,J=7.5Hz, 2H), 3.19(quintet, J=6.6Hz, 4H), 1.97(quintet, J=7.2Hz, 2H),1.66(sextet, J=7.5Hz, 2H), 1.4(s, 9 H), 1.16(t, J=7.8Hz, 3H); 60 MS(CI)m/e 389 ¹H NMR(300MHz, DMSO-d₆) δ 8.06(d, J=8.1Hz, 1 (M + H) H), 7.65(d,J=7.8Hz, 1H), 7.43(t, J=6.9Hz, 1H), 7.24(t, J=6.9Hz, 1H), 6.51(s, 2H),4.96(t, J=7.5Hz, 2H), 3.66(t, J=7.5Hz, 2H), 3.01(t, J=8.1Hz, 2 H),1.82(quintet, J=7.5Hz, 2H), 1.48(sextet, J=7.5Hz, 2H), 1.32(s, 9H),0.97(t, J=7.2Hz, 3H); 61 MS(CI) m/e 343 ¹H NMR(300MHz, DMSO-d₆) δ7.99(d, J=7.8Hz, 1 (M + H) H), 7.62(d, J=7.5Hz, 1H), 7.41(t, J=7.8Hz,1H), 7.24(t, J=6.6Hz, 1H), 6.46(s, 2H), 4.70(t, J=7.5Hz, 2H), 2.98(t,J=6.9Hz, 4H), 2.45(t, J=7.5Hz, 2 H), 1.80(quintet, J=7.8Hz, 2H),1.46(sextet, J=7.2Hz, 4H), 0.96(t, J=7.5Hz, 3H), 0.86(t, J=7.5Hz, 3 H);62 MS(CI) m/e 375 ¹H NMR(300MHz, DMSO-d₆) δ 8.06(d, J=8.7Hz, 1 (M + H)H), 7.64(d, J=7.5Hz, 1H), 7.44(t, J=6.6Hz, 1H), 7.25(t, J=6.9Hz, 1H),6.49(s, 2H), 4.95(t, J=7.5Hz, 2H), 3.72(t, J=7.2Hz, 2H), 3.18(m, 2H),2.99 (t, J=7.5Hz, 2H), 1.82(quintet, J=8.1Hz, 2H), 1.69 (sextet,J=8.4Hz, 2H), 1.47(sextet, J=7.5Hz, 2H), 0.97(t, J=7.2Hz, 3H), 0.96(t,J=7.5Hz, 3H); 63 MS(CI) m/e 357 ¹H NMR(300MHz, DMSO-d₆) δ 7.99(d,J=7.2Hz, 1 (M + H) H), 7.62(d, J=6.6Hz, 1H), 7.41(t, J=6.9Hz, 1H),7.24(t, J=6.9Hz, 1H), 6.47(s, 2H), 4.70(t, J=6.9Hz, 2H), 2.97(t,J=8.4Hz, 4H), 2.35(d, J=6.6Hz, 2 H), 1.81(quintet, J=7.5Hz, 2H),1.63(septet, J=6.6Hz, 1H), 1.46(sextet, J=7.5Hz, 2H), 0.96(t, J=7.5Hz,3H), 0.87(d, J=6.6Hz, 6H); 64 MS(CI) m/e 389 ¹H NMR(300MHz, DMSO-d₆) δ8.06(d, J=7.5Hz, 1 (M + H) H), 7.64(d, J=8.1Hz, 1H), 7.43(t, J=6.6Hz,1H), 7.23(t, J=6.9Hz, 1H), 6.51(s, 2H), 4.94(t, J=6.6Hz, 2H), 3.72(t,J=7.8Hz, 2H), 3.13(d, J=6.6Hz, 2 H), 2.99(t, J=7.5Hz, 2H), 2.21(septet,J=6Hz, 1 H), 1.81(quintet, J=8.4Hz, 2H), 1.47(sextet, J=7.5Hz, 2H),1.00(m, 9H); 65 MS(CI) m/e 329 ¹H NMR(300MHz, DMSO-d₆) δ 8.00(d,J=8.4Hz, 1 (M + H) H), 7.62(d, J=8.4Hz, 1H), 7.42(t, J=8.4Hz, 1H),7.25(t, J=8.4Hz, 1H), 6.47(s, 2H), 4.71(t, J=7.5Hz, 2H), 2.99(q,J=7.8Hz, 4H), 2.53(m, 2H), 1.81 (quintet, J=7.8Hz, 2H), 1.46(sextet,J=7.2Hz, 2H), 1.12(t, J=7.2Hz, 3H), 0.97(t, J=7.2Hz, 3H); 66 MS(CI) m/e361 ¹H NMR(300MHz, DMSO-d₆) δ 8.06(d, J=6.9Hz, 1 (M + H) H), 7.63(d,J=6.9Hz, 1H), 7.43(t, J=6.9Hz, 1H), 7.25(t, J=6.9Hz, 1H), 6.48(s, 2H),4.95(t, J=7.2Hz, 2H), 3.72(t, J=7.2Hz, 2H), 3.22(quartet, J=7.5, 2H),2.99(t, J=7.5Hz, 2H), 1.81(quintet, J=7.2Hz, 2H), 1.44(sextet, J=6.9Hz,2H), 1.21(t, J=7.5Hz, 3 H), 0.97(t, J=7.5Hz, 3H);

EXAMPLE 672-butyl-1-[2-(methylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0453]

Part A

[0454] Using the general method of Example 21 Part D,2-butyl-1-(2-chloroethyl)-1H-imidazo[4,5-c]quinoline-4-amine (1.44 g,4.76 mmol) was reacted with sodium thiomethoxide (0.42 g of 95%, 5.71mmol) to provide 1.4 g of2-butyl-1-[2-(methylthio)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine as anoff-white powder.

Part B

[0455] Using the general method of Example 5,2-butyl-1-[2-(methylthio)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.35g, 4.29 mol) was oxidized. The crude product was purified bychromatography (silica gel eluting with 95/5 dichloromethane/methanol)then triturated with diethyl ether to provide 0.5 g of2-butyl-1-[2-(methylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine asa white powder, m.p. 226-228° C.

[0456] Analysis: Calculated for C₁₇H₂₂N₄O₂S: % C, 58.94; % H, 6.40; % N,16.17; Found: % C, 58.91; % H, 6.27; % N, 16.13. ¹H NMR (300 MHz,DMSO-d₆) δ 8.05 (d, J=8.1 Hz, 1 H), 7.63 (d, J=8.1 Hz, 1 H), 7.44 (t,J=8.4, Hz, 1 H), 7.26 (t, J=8.1, Hz, 1 H), 6.48 (s, 2 H), 4.95 (t, J=7.2Hz, 2 H), 3.77 (t, J=7.2 Hz, 2 H), 3.11 (s, 3 H), 2.99 (t, J=7.8 Hz, 2H), 1.83 (quintet, J=7.6 Hz, 2 H), 1.48 (sextet, J=7.4 Hz, 2 H), 0.97(t, J=7.5 Hz, 3 H); MS(CI) m/e 347 (M+H).

EXAMPLE 682-methyl-1-[6-(methylsulfonyl)hexyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0457]

Part A

[0458] A solution of thionyl chloride (6.74 g, 56.6 mmol) indichloromethane (50 mL) was slowly added to a solution ofN-(6-hydroxyhexyl)-3-nitroquinolin-4-amine (14.9 g, 51.5 mmol) indichloromethane (200 mL). After the addition was complete the reactionmixture was stirred for about an hour and then it was concentrated underreduced pressure. The residue was suspended in water, slurried for aboutan hour, isolated by filtration, washed with water and then dried toprovide 14.0 g of N-(6-chlorohexyl)-3-nitroquinolin-4-amine as a solid.

Part B

[0459] Using the general method of Example 1 Part C,4-(6-chlorohexyl)-3-nitroquinolin-4-amine (6 g, 19 mmol) was reduced toprovide N⁴-(6-chlorohexyl)quinoline-3,4-diamine.

Part C

[0460] N⁴-(6-Chlorohexyl)quinoline-3,4-diamine (5 g, 18 mmol), triethylorthoacetate (2.92 g, 18 mmol), toluene (75 mL), and a catalytic amountof pyridine hydrochloride were combined in a pressure vessel and heatedto 140° C. After about 1.5 hours the reaction mixture was allowed tocool and then it was concentrated under reduced pressure to provide 3.8g of 1-(6-chlorohexyl)-2-methyl-1H-imidazo[4,5-c]quinoline as a darkorange oil.

Part D

[0461] Using the general method of Examples 43-55 Part B,1-(6-chlorohexyl)-2-methyl-1H-imidazo[4,5-c]quinoline (3.8 g, 13 mol)was oxidized and then aminated to provide 2.5 g of1-(6-chlorohexyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine.

Part E

[0462] 1-(6-Chlorohexyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.5g, 8 mmol), sodium thiomethoxide (1.13 g, 15.5 mmol) andN,N-dimethylformamide (15 mL) were combined and heated at 160° C. for 3hours. The reaction was quenched with water and the precipitate isolatedto provide 1.5 g of2-methyl-1-[6-(methylthio)hexyl]-1H-imidazo[4,5-c]quinolin-4-amine.

Part F

[0463] Using the general method of Example 38, the material from Part Ewas oxidized to provide 0.80 g of2-methyl-1-[6-(methylsulfonyl)hexyl]-1H-imidazo[4,5-c]quinolin-4-amine,m.p. 202-206° C.

[0464] Analysis: Calculated for C₁₈H₂₄N₄O₂S.0.02 EtOH: % C, 59.96; % H,6.73; % N, 15.50; Found: % C, 59.74; % H, 6.81; % N, 15.30. ¹H NMR (300MHz, DMSO-d₆) δ 8.02 (d, J=8.1 Hz, 1 H), 7.62 (d, J=7.2 Hz, 1 H), 7.41(t, J=8.1 Hz, 1 H), 7.25 (t, J=7.2 Hz, 1 H), 6.48 (s, 2 H), 4.48 (t,J7.2 Hz, 2 H), 3.08 (t, J=8.4 Hz, 2 H), 2.92 (s, 3 H), 2.60 (s, 3 H),1.82 (m, 2 H), 1.68 (m, 2 H) 1.44 (m, 4 H); MS (CI) m/e 361 (M+H).

EXAMPLE 691-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0465]

Part A

[0466] Using the general method of Example 37 Part D,N-(5-chloropentyl)-3-nitroquinolin-4-amine (10 g, 34 mmol) was reactedwith benzenethiol (1.1 eq) to provide 12.6 g of3-nitro-N-[5-(phenylthio)pentyl]quinolin-4-amine as a solid.

Part B

[0467] Using the general method of Example 1 Part C, the material fromPart A was reduced to provideN⁴-[5-(phenylthio)pentyl]quinoline-3,4-diamine as a brown crystallinesolid.

Part C

[0468] Using the general method of Example 1 Part D,N⁴-[5-(phenylthio)pentyl]quinoline-3,4-diamine (5.1 g, 15.1 mmol) wascyclized using triethyl orthoformate (2.46 g, 16.6 mmol) in the presenceof a catalytic amount of pyridine hydrochloride to provide1-[5-(phenylthio)pentyl]-1H-imidazo[4,5-c]quinoline as a yellow solid.

Part D

[0469] Using the general method of Example 11 Part F except thatdichloromethane was used as a solvent instead of chloroform,1-[5-(phenylthio)pentyl]-1H-imidazo[4,5-c]quinoline (5 g, 13.2 mmol) wasoxidized to provide 4.7 g1-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline 5N-oxide as anoil.

Part E

[0470] Trichloroacetyl isocyanate (1.91 g, 10 mmol) was added slowly toa solution of 1-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline5N-oxide (3.6 g, 9.1 mmol) in dichloromethane (40 mL). The reactionmixture was concentrated under reduced pressure. The residue wasdissolved in methanol then combined with about 2 equivalents of sodiummethoxide. After several minutes a precipitate formed. The precipitatewas isolated by filtration and then recrystallized from ethanol. Thismaterial was purified by chromatography (silica gel eluting with 4%methanol in dichloromethane) to provide 0.3 g of1-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-4-amine as asolid, m.p. 171-172° C.

[0471] Analysis: Calculated for C₂₁H₂₂N₄O₂S: % C, 63.94; % H, 5.62; % N,14.20; Found: % C, 63.72; % H, 5.64; % N, 14.07. ¹H NMR (300 MHz,DMSO-d₆) δ 8.15 (s, 1 H), 7.99(d, J=8.1 Hz, 1 H), 7.86 (m, 2 H), 7.71(m, 1 H), 7.64 (m, 3 H), 7.43 (t, J=6.6 Hz, 1 H); 7.22 (t, J=6.9 Hz, 1H), 6.57 (s, 2 H), 4.54 (t, J=7.5 Hz, 2 H), 3.30 (m, 2 H), 1.84(quintet, J=7.5 Hz, 2 H), 1.57 (quintet, J=6.9 Hz, 2 H), 1.40 (quintet,J=6.9 Hz, 2 H); MS (CI) m/e 395 (M+H).

EXAMPLE 702-(2-methoxyethyl)-1-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0472]

Part A

[0473] A solution of 3-methoxypropanoyl chloride (2.04 g, 16.6 mmol) inpyridine (20 mL) was slowly added to a chilled (0° C.) solution ofN⁴-[5-(phenylthio)pentyl]quinoline-3,4-diamine (5.1 g, 15.2 mmol) inpyridine. The reaction was allowed to warm to ambient temperature. Moreacid chloride (1 g) was added and the reaction was heated at refluxovernight. The reaction mixture was concentrated under reduced pressureto provide 6.7 g of3-methoxy-N-(4-{[5-(phenylthio)pentyl]amino}quinolin-3-yl)propanamide asa sticky brown solid.

Part B

[0474] The material from Part A was combined with pyridine and thenrefluxed for several hours. The reaction mixture was concentrated underreduced pressure. The residue was partitioned between dichloromethaneand water. The organic layer was washed with water (3×100 mL), filteredthrough a layer of Celite®D filter aid, and then concentrated underreduced pressure. The residue was purified by chromatography (silica geleluting with 4/1 dichloromethane/methanol) to provide 3.7 g of2-(2-methoxyethyl)-1-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline.

Part C

[0475] Using the general method of Example 37 Part B, the material fromPart B was oxidized to provide 2.09 g of2-(2-methoxyethyl)-1-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-5N-oxide.

Part D

[0476] Using the general method of Example 37 Part C, the material fromPart C was aminated. The crude product was recrystallized from ethanolto provide 0.26 g of2-(2-methoxyethyl)-1-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine,m.p. 172-175° C.

[0477] Analysis: Calculated for C₂₄H₂₈N₄O₃S: % C, 63.69; % H, 6.24; % N,12.38; Found: % C, 63.40; % H, 5.95; % N, 12.08. ¹H NMR (300 MHz,DMSO-d₆) δ 7.96 (d, J=6.6 Hz, 1 H), 7.87 (d, J=5.4 Hz, 2 H), 7.73 (m, 1H), 7.63 (m, 3 H), 7.41 (t, J=7.8 Hz, 1 H), 7.22 (t, J=7.8 Hz, 1 H),6.47 (s, 2 H), 4.46 (t, J=7.5Hz, 2 H), 3.80 (t, J=6.9Hz, 2 H), 3.27 (s,3 H), 3.14 (t, J=6 Hz, 2 H), 1.76 (m, 2 H), 1.53 (m, 4 H); MS (CI) m/e473 (M+H).

EXAMPLE 711-[5-(methylsulfonyl)pentyl]-2-(trifluoromethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0478]

Part A

[0479] A cool solution of trifluoroacetyl chloride (3.5 g, 26.5 mmol) intoluene was slowly added to a solution ofN4-[5-(methylthio)pentyl]quinoline-3,4-diamine (6 g, 23.1 mmol) in amixture of toluene and pyridine. A heavy yellow precipitate formed. Thereaction mixture was stirred over the weekend and then concentratedunder reduced pressure to provide 13.2 g of crude2,2,2-trifluoro-N-(4-{[5-(methylthio)pentyl]amino}quinolin-3-yl)acetamide.

Part B

[0480] The material from Part A was combined with toluene (150 mL) in apressure vessel and then heated at 140° C. for about 30 minutes. Thereaction mixture was concentrated under reduced pressure. The residuewas partitioned between dichloromethane and 5% sodium carbonate. Theorganic layer was washed with water, dried over magnesium sulfate andthen concentrated under reduced pressure to provide 7.9 g of1-[5-(methylthio)pentyl]-2-(trifluoromethyl)-1H-imidazo[4,5-c]quinolineas a solid.

Part C

[0481] Using the general method of Example 11 Part F, the material fromPart B was oxidized to provide 7.5 g of1-[5-(methylsulfonyl)pentyl]-2-(trifluoromethyl)-1H-imidazo[4,5-c]quinoline-5N-oxide.

Part D

[0482] Using the general method of Example 37 Part C, the material fromPart C was aminated to provide 2.5 g of1-[5-(methylsulfonyl)pentyl]-2-(trifluoromethyl)-1H-imidazo[4,5-c]quinolin-4-amineas a solid, m.p. 192-195° C.

[0483] Analysis: Calculated for C₁₇H₁₉F₃N₄O₂S:.0.05 CH₂Cl₂: % C, 50.61;% H, 4.76; % N, 13.84; found: % C, 50.60; % H, 4.76; % N, 13.77. ¹H NMR(300 MHz, DMSO-d₆) δ 8.08 (d, J=7.2 Hz, 1 H), 7.67 (d, J=7.5 Hz, 1 H),7.54 (t, J=6.9 Hz, 1 H), 7.34 (t,J=7.8 Hz, 1 H), 6.91 (s, 2 H), 4.67(t,J=8.4 Hz, 2 H), 3.11 (t, J=7.5 Hz, 2 H), 2.93 (s, 3 H), 1.91(quintet, J=7.2 Hz, 2 H), 1.744 (quintet, J=8.1 Hz, 2 H), 1.58 (quintet,J=6.9 Hz, 2 H); MS (CI) m/e 401 (M+H).

EXAMPLE 722-ethyl-1-[4-(pyrimidin-2-ylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0484]

[0485] Using the general method of Example 20 Part A,1-(4-chlorobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.30mmol) was reacted with 2-mercaptopyrimidine (0.59 g, 5.3 mmol) toprovide 1.0 g of2-ethyl-1-[4-(pyrimidin-2-ylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amineas an off white powder, m.p. 182-185° C.

[0486] Analysis: Calculated for C₂₀H₂₂N₆S.0.25 H₂O: % C, 62.72; % H,5.92; % N, 21.94; Found: % C, 63.00; % H, 5.88; % N, 22.21.

EXAMPLE 732-ethyl-1-[4-(pyrimidin-2-ylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0487]

[0488] Using the general method of Example 5 Part A,2-ethyl-1-[4-(pyrimidin-2-ylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine(0.3 g) was oxidized to provide 10 mg of2-ethyl-1-[4-(pyrimidin-2-ylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amineas a peach solid, m.p. 172-175° C.

[0489] Analysis: Calculated for C₂₀H₂₂N₆O₂.0.25 H₂0: % C, 57.88; % H,5.46; % N, 20.25; Found: % C, 57.76; % H, 5.48; % N, 19.88.

EXAMPLE 742-methyl-1-[4-(methylsulfonyl)butyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine

[0490]

[0491] Catalyst (0.2 g of platinum oxide) was added to solution of2-methyl-1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine(1.0 g) in trifluoroacetic acid (11 mL) in a Parr hydrogenation flask.The resulting mixture was placed under hydrogen pressure (50 psi, 3.5Kg/cm²) for about 90 hours. The reaction mixture was filtered through alayer of Celite® filter aid which had been prewashed withtrifluoroacetic acid (˜125 mL). The filter cake was washed withtrifluoroacetic acid (˜100 mL). The filtrate was concentrated underreduced pressure. The resulting oil was dissolved in 1 N hydrochloricacid (20 mL). After several minutes a white precipitate formed. The pHwas brought to 14 with aqueous 50% sodium hydroxide. The precipitatedissolved to provide a yellow solution; shortly thereafter a precipitateformed. The resulting suspension was allowed to stir at ambienttemperature overnight then it was cooled in an ice/water bath for 2hours and then filtered to provide 1.0 g of a white powder. Thismaterial was purified by recrystallization from methanol followed bycolumn chromatography (silica gel eluting with 9/1dichloromethane/methanol) to provide 0.44 g of2-methyl-1-[4-(methylsulfonyl)butyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, m.p. 213-216° C.

[0492] Analysis: Calculated for C₁₆H₂₄N₄O₂S: % C, 57.12; % H, 7.19; % N,16.65; Found: % C, 56.86; % H, 7.09; % N, 16.61.

EXAMPLE 752-methyl-1-[5-(methylsulfonyl)pentyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine

[0493]

[0494] Using the general method of Example 74,2-methyl-1-[4-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine(1.3 g) was reduced and purified to provide 0.6 g of2-methyl-1-[5-(methylsulfonyl)pentyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amineas white needles, m.p. 172-174° C.

[0495] Analysis: Calculated for C₁₇H₂6N₄O₂S: % C, 58.26; % H, 7.48; % N,15.99; Found: % C, 58.22; % H, 7.54; % N, 16.12.

EXAMPLE 762-methyl-1-{4-[(1-methylethyl)sulfonyl]butyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine

[0496]

Part A

[0497] A suspension of 2,4-dihydroxy-3-nitro-6,7,8,9-tetrahydroquinoline(10.56 g, 50.3 mmol) in phosphorous oxychloride (60 mL) was heated at50-60° C. for 48 hours. The reaction mixture was allowed to cool toambient temperature then it was slowly added with vigorous stirring toan ice cooled biphasic mixture of dichloromethane (300 mL) and aqueous20% sodium carbonate (500 mL). The mixture was made basic (pH 8) withsolid sodium carbonate and the layers were separated. The aqueous layerwas extracted with dichloromethane (2×125 mL). The combined organicswere dried over magnesium sulfate and then concentrated under reducedpressure to provide 11.9 g of2,4-dichloro-3-nitro-6,7,8,9-tetrahydroquinoline as a light brown solid.

Part B

[0498] Triethylamine (6.1 mL, 1.2 eq) was added to a solution of2,4-dichloro-3-nitro-6,7,8,9-tetrahydroquinoline (9.0 g, 36.4 mmol, 1eq) in N,N-dimethylformamide (60 mL). 4-Amino-1-butanol (3.7 mL, 1.1 eq)was added and the reaction mixture was heated at ˜50° C. for 5 hours.The reaction mixture was allowed to cool to ambient temperature and thenit was concentrated under reduced pressure to provide a red oil. The oilwas diluted with chloroform (500 mL), washed with water (3×200 mL) andbrine (1×200 mL) then dried over magnesium sulfate and concentratedunder reduced pressure to provide 11.9 g of a red oil. The oil wastriturated with diethyl ether (40 mL). The resulting solid was isolatedby filtration then washed with diethyl ether (3×10 mL) to provide 5.76 gof 4-[(2-chloro-3-nitro-6,7,8,9-tetrahydroquinolin-4-yl)amino]butan-1-olas a light yellow solid.

Part C

[0499] Phenol (2.71 g, 1.5 eq) was added in portions over a period of 15minutes to a suspension of sodium hydride (1.15 g of 60%, 1.5 eq) indiglyme (34 mL). The reaction mixture was stirred for an additional 30minutes and then4-[(2-chloro-3-nitro-6,7,8,9-tetrahydroquinolin-4-yl)amino]butan-1-ol(5.75 g, 19.16 mmol, 1.0 eq) was added as a solid. The reaction mixturewas heated at 85° C. for 24 hours and then allowed to cool to ambienttemperature overnight. The reaction mixture was concentrated to a volumeof ˜10 mL under reduced pressure. The concentrate was diluted withchloroform (400 mL), washed with aqueous 5% sodium hydroxide (1×75 mL)and water (2×100 mL) then dried over magnesium sulfate and concentratedunder reduced pressure. The residue was dissolved in acetonitrile (200mL), washed with hexanes (2×100 mL) and concentrated under reducedpressure to provide 5.31 g of4-[(3-nitro-2-phenoxy-6,7,8,9-tetrahydroquinolin-4-yl)amino]butan-1-olas a dark oil.

Part D

[0500] N-Chlorosuccinimide (2.38 g, 1.2 eq) was added to a solution oftriphenylphosphine (4.68 g, 1.2 eq) in tetrahydrofuran (30 mL). Thereaction mixture was stirred for 20 minutes and then a solution of thematerial from Part C in tetrahydrofuran (30 mL) was added. The reactionmixture was stirred for 75 minutes and then concentrated under reducedpressure. The residue was diluted with chloroform (350 mL), washed withwater (2×150 mL), dried over magnesium sulfate and then concentratedunder reduced pressure. The residue was purified by chromatography(silica gel eluting with chloroform) to provide 4.88 g ofN4-(4-chlorobutyl)-3-nitro-2-phenoxy-6,7,8,9-tetrahydroquinolin-4-amineas a yellow solid.

Part E

[0501] Nickel(II)chloride hexahydrate (303 mg, 0.1 eq) was added to asuspension ofN⁴-(4-chlorobutyl)-3-nitro-2-phenoxy-6,7,8,9-tetrahydroquinolin-4-amine(4.78 g, 12.71 mmol, 1.0 eq) in 1:1 methanol:chloroform (120mL). Themixture was cooled to 0° C. Sodium borohydride (1.92 g, 4 eq) was addedin 4 equal portions over a period of 50 minutes. The reaction mixturewas stirred for an additional 30 minutes and then it was concentratedunder reduced pressure. The residue was dissolved in chloroform (300mL), washed with water (3×100 mL), dried over magnesium sulfate and thenconcentrated under reduced pressure to provide 5.01 g ofN⁴-(4-chlorobutyl)-2-phenoxy-6,7,8,9-tetrahydroquinoline-3,4-diamine asa thick oil.

Part F

[0502] Trimethylorthoacetate (2.0 mL, 1.2 eq) was added to a solution ofthe material from Part E in toluene (40 mL). Pyridine hydrochloride (150mg, 0.1 eq) was added and the reaction mixture was heated at 100° C. for1 hour. The reaction mixture was cooled to ambient temperature and thenconcentrated under reduced pressure. The residue was dissolved inchloroform (300 mL), washed with water (2×75 mL), dried over magnesiumsulfate, concentrated under reduced pressure, diluted with acetonitrile(40 mL) and then concentrated under reduced pressure to provide 4.5 g ofa dark red semisolid. This material was purified on silica eluting with2:98 methanol:chloroform to provide a red oil. The oil was diluted withisopropanol (50 mL), concentrated and then triturated with diethylether. The resulting solid was isolated by filtration and washed withdiethyl ether to provide 2.77 g of1-(4-chlorobutyl)-2-methyl-4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolineas a white solid.

Part G

[0503] 1-Methylethylthiol (57 μL, 1.2 eq) was added dropwise to asuspension of sodium hydride (25 mg of 60%, 1.2 eq) inN,N-dimethylformamide (1 mL). The reaction mixture was stirred for 30minutes and then a solution of1-(4-chlorobutyl)-2-methyl-4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline(189 mg, 0.51 mmol, 1.0 eq) in N,N-dimethylformamide (1.5 mL) was added.The reaction mixture was stirred for 3 hours then it was diluted withchloroform (50 mL), washed with aqueous 5% sodium hydroxide (1×50 mL)and water (1×25 mL), dried over magnesium sulfate and then concentratedunder reduced pressure to provide 176 mg of1-{[4-(1-methylethyl)thio]butyl}-2-methyl-4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolineas a light brown oil.

Part H

[0504] 3-Chloroperbenzoic acid (218 mg, 2.2 eq at 75% titer) was addedto a chilled (0° C.) solution of the material from Part G in chloroform(2.2 mL). The reaction mixture was stirred at 0° C. for 20 minutes andthen it was diluted with chloroform (50 mL), washed with aqueoussaturated sodium carbonate (2×25 mL), dried over magnesium sulfate andthen concentrated under reduced pressure to provide 202 mg of1-{[4-(1-methylethyl)sulfonyl]butyl}-2-methyl-4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolineas a yellow semisolid.

Part I

[0505] A mixture of 1-{[-(1-methylethyl)sulfonylbutyl}-2-methyl-4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline(200 mg) and solid ammonium acetate (2.1 g) were heated at 145° C. in asealed tube for 24 hours. The reaction was cooled to ambient temperaturethen it was diluted with chloroform (40 mL) and washed with aqueous 10%sodium hydroxide (2×20 mL). The aqueous layer was extracted withchloroform (2×20 mL). The combined organics were dried over magnesiumsulfate and then concentrated under reduced pressure to provide 204 mgof a yellow oil. The oil was triturated with acetonitrile to provide 48mg of an off white solid. The mother liquor was concentrated and theresidue purified by chromatography (silica gel eluting with 10:90methanol:chloroform) followed by trituration with acetonitrile toprovide 18 mg of a solid. The two solids were combined,rechromatographed and then recystallised from ethanol. The resultantprisms were concentrated from methanol to provide 40 mg of2-methyl-1-{4-[(1-methylethyl)sulfonyl]butyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amineas a white powder, m.p. 177-178° C.

[0506] Analysis: Calculated for C₁₈H₂₈N₄O₂S: % C, 59.31; % H, 7.74; % N,15.37; Found: % C, 59.27; % H, 7.82; % N, 15.19. ¹H NMR (300 MHz,DMSO-d₆): δ 5.64 (s, 2H); 4.21 (m, 2H); 3.21 (septet, 1H, J=6.9 Hz);3.14 (m, 2H); 2.94 (m, 2H); 2.65 (m, 2H); 2.47 (s, 3H); 1.76 (br m, 8H);1.23 (d, 6H, J=6.6 Hz). EIMS (m/z): 365 (M+1).

EXAMPLE 772-methyl-1-{4-[(4-fluorophenyl)sulfonyl]butyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine

[0507]

Part A

[0508] Using the general method of Example 76 Part G,1-(4-chlorobutyl)-2-methyl-4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline(740 mg, 2.00 mmol, 1.0 eq) was reacted with 4-fluorobenzenethiol (260FL, 1.2 eq) to provide 0.91 g of1-{[4-(4-fluorophenyl)1thio]butyl}-2-methyl-4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolineas a light yellow solid.

Part B

[0509] Using the general method of Example 76 Part H, the material fromPart A was oxidized to provide 1.02 g of1-{[4-(4-fluorophenyl)sulfonyl]butyl)-2-methyl-4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolineas a white foam.

Part C

[0510] Using the general method of Example 76 Part I, the material fromPart B was aminated to provide 148 mg of2-methyl-1-{4-[(4-fluorophenyl)sulfonyl]butyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, m.p. softened at 137-144° C. then melted at 159-162°C.

[0511] Analysis: Calculated for C₂₁H₂₅FN₄O₂S.H₂O: % C, 58.05; % H, 6.26;% N, 12.98; Found: % C, 57.78; % H, 5.93; % N, 12.72. ¹H NMR (300 MHz,DMSO-d₆): δ 7.93 (m, 2H); 7.50 (m, 2H); 5.67 (s, 2H); 4.15 (m, 2H); 3.41(m, 2H), 2.87 (br m, 2H); 2.64 (br m, 2H); 2.41 (s, 3H); 1.74 (br m,8H). EIMS (m/z): 417 (M+1).

EXAMPLE 782-methyl-1-{4-[(1,1-dimethylethyl)sulfonyl]butyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine

[0512]

Part A

[0513] Using the general method of Example 76 Part G,1-(4-chlorobutyl)-2-methyl-4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline(750 mg, 2.03 mmol, 1.0 eq) was reacted with 1,1-dimethylethylthiol (275μL, 1.2 eq) to provide 0.91 g of1-{[4-(1,1-dimethylethyl)1thio]butyl}-2-methyl-4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolineas an oil which crystallized on standing.

Part B

[0514] Using the general method of Example 76 Part H, the material fromPart A was oxidized to provide 1.0 g of1-{[4-(1,1-dimethylethyl)sulfonyl]butyl}-2-methyl-4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolineas a light yellow foam.

Part C

[0515] Using the general method of Example 76 Part I, the material fromPart B was aminated to provide 460 mg of2-methyl-1-{4-[(1,1-dimethylethyl)sulfonyl]butyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, m.p. 208-210° C.

[0516] Analysis: Calculated for C₁₉H₃₀N₄O₂S: % C, 60.29; % H, 7.99; % N,14.80; Found: % C, 60.26; % H, 7.88; % N, 14.89. ¹H NMR (300 MHz,DMSO-d₆): δ 5.65 (s, 2H); 4.23 (m, 2H); 3.13 (m, 2H); 2.95 (br m, 2H);2.65 (br m, 2H); 2.47 (s, 3H); 1.75 (br m, 8H). EIMS (m/z): 379 (M+1).

EXAMPLE 792-ethoxymethyl-1-(4-methanesulfonyl-butyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine

[0517]

Part A

[0518] Sodium thiomethoxide (205 mg, 1.1 eq.) was added to a solution of1-(4-chlorobutyl)-2-methyl-4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline(1.00 g, 2.66 mmol, 1.0 eq.) in DMF (13 mL). The reaction was stirredfor 1 hour, then concentrated under reduced pressure. The residue wasdissolved in methylene chloride (110 mL), washed with water (1×30 mL),dried over magnesium sulfate and concentrated under reduced pressure toprovide 0.97 g of(4-methylsulfanyl-butyl)-(3-nitro-2-phenoxy-5,6,7,8-tetrahydro-quinolin-4-yl)-amineas a yellow solid.

Part B

[0519] Using the general method of Example 76 Part E, the material fromPart A was reduced to provide 0.89 g ofN⁴-(4-methylsulfanyl-butyl)-2-phenoxy-5,6,7,8-tetrahydro-quinoline-3,4-diamineas a clear colorless oil.

Part C

[0520] Ethoxyacetyl chloride was added to a solution of the materialfrom Part B in pyridine (10 mL). After stirring at ambient temperaturefor 1 hour, the reaction was heated at 95° C. for 1 hour, then 105° C.for 4 hours. The reaction mixture was cooled to ambient temperature andconcentrated under reduced pressure. The residue was dissolved inmethylene chloride (100 mL), washed with saturated aqueous sodiumbicarbonate (1×25 mL), dried over magnesium sulfate and concentratedunder reduced pressure to provide 0.89g of2-ethoxymethyl-1-(4-methylsulfanyl-butyl)-4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolineas a light yellow oil.

Part D

[0521] Using the general method of Example 76 Part H, the material fromPart C was oxidized to provide 0.60 g of2-ethoxymethyl-1-(4-methanesulfonyl-butyl)-4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolineas a light brown foam.

Part E

[0522] Using the general method of Example 76 Part I, the material fromPart D was aminated to provide 355 mg of2-ethoxymethyl-1-(4-methanesulfonyl-butyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amineas an off white solid, m.p. 170-171° C.

[0523] Analysis: Calculated for C₂₄H₃₁N₃O₄S: % C, 56.82; % H, 7.42; % N,14.72; Found: % C, 56.64; % H, 7.32; % N, 14.47. ¹H NMR (300 MHz,DMSO-d₆): δ 5.89 (br s, 2H); 4.64 (s, 2H); 4.29 (m, 2H); 3.51 (q, 2H,J=7.0 Hz); 3.17 (m, 2H); 2.96 (br s,5H); 2.67 (m, 2H); 1.80 (m, 8H);1.15 (t, 3H) J=7.0 Hz). EIMS (m/z): 381 (M+1).

[0524] Additional compounds that could be prepared using the methodsdescribed above include:

[0525]2-butyl-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0526]2-butyl-1-[2-(phenylthio)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0527]2-butyl-1-[4-(phenylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0528]2-butyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0529]2-butyl-1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0530] 1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0531] 1-[2-(phenylthio)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0532] 1-[4-(phenylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0533] 1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0534] 1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0535]2-butyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0536] 1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0537]2-ethyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0538]2-methyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0539]2-hexyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0540]2-methoxyethyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0541]2-butyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0542]2-butyl-1-[5-(methylsulfinyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0543]2-butyl-1-[3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0544]2-butyl-1-[3-(phenylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0545]2-propyl-1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0546]2-butyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0547]2-butyl-1-[3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0548]2-methyl-1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0549]2-ethyl-1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0550] 1-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0551]2-methyl-1-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0552]2-ethyl-1-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0553] 2-propyl-1-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0554]2-butyl-1-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0555]2-(2-cyclopropylethyl)-1-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0556]2-(2-cyclopropylethyl)-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0557]2-cyclopropylmethyl-1-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0558]2-cyclopropylmethyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0559]2-methoxyethyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0560]2-methoxyethyl-1-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0561]2-ethoxymethyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0562]2-propyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0563]2-methyl-1-[3-(methylthio)propyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0564]2-methyl-1-[3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0565]2-ethyl-1-[3-(methylthio)propyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0566]2-methyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0567]2-methyl-1-[4-(methylsulfinyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0568]2-ethyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0569]2-propyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0570]2-butyl-1-[4-(methylsulfinyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0571]2-methyl-1-[(2-methylthio)ethyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0572]2-ethyl-1-[(2-methylthio)ethyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0573]2-propyl-1-[(2-methysulfonyl)ethyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0574]2-butyl-1-{4-[(2,4-difluorophenyl)thio]butyl}-1H-imidazo[4,5-c]quinolin-4-amine;

[0575]2-butyl-1-{4-[(2,4-difluorophenyl)sulfonyl]butyl}-1H-imidazo[4,5-c]quinolin-4-amine;

[0576]2-butyl-1-[4-(ethylsulfonyl)butyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0577]2-butyl-1-[4-(tert-butylsulfonyl)butyl]-1H-imidazo[4,5-c]quinoline-4-amine;

[0578]2-butyl-1-{4-[(4-fluorophenyl)thio]butyl}-1H-imidazo[4,5-c]quinolin-4-amine;

[0579]2-butyl-1-{4-[(4-fluorophenyl)sulfonyl]butyl}-1H-imidazo[4,5-c]quinolin-4-amine;

[0580]4-amino-2-methyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-8-ol;

[0581]2-ethyl-1-{4-[(1-methylethyl)thio]butyl}1H-imidazo[4,5-c]quinoline-4-amine;

[0582]2-ethyl-1-{4-[(3,5-dichlorophenyl)thio]butyl}1H-imidazo[4,5-c]quinoline-4-amine;

[0583]2-ethyl-1-[4-(cyclopentylsulfonyl)butyl]1H-imidazo[4,5-c]quinoline-4-amine;

[0584]2-ethyl-1-{4-[(3,5-dichlorophenyl)sulfonyl]butyl}1H-imidazo[4,5-c]quinoline-4-amine;

[0585]2-ethyl-1-[4-(propylthio)butyl]1H-imidazo[4,5-c]quinoline-4-amine;

[0586]2-ethyl-1-{4-[(4-chlorophenyl)thio]butyl}1H-imidazo[4,5-c]quinoline-4-amine;

[0587] 2-ethyl-1-[4-(butylthio)butyl]1H-imidazo[4,5-c]quinoline-4-amine;

[0588]2-ethyl-1-{4-[(4-fluorophenyl)thio]butyl}1H-imidazo[4,5-c]quinoline-4-amine;

[0589]2-ethyl-1-{4-[(4-chlorophenyl)sulfonyl]butyl}1H-imidazo[4,5-c]quinoline-4-amine;

[0590] 2-ethyl-1-[4-(ethylthio)butyl]1H-imidazo[4,5-c]quinoline-4-amine;

[0591]2-ethyl-1-[4-(ethylsulfonyl)butyl]1H-imidazo[4,5-c]quinoline-4-amine;

[0592]2-ethyl-1-[4-(cyclohexylsulfonyl)butyl]1H-imidazo[4,5-c]quinoline-4-amine;

[0593]2-butyl-1-{2-[(1-methylethyl)sulfonyl]ethyl}1H-imidazo[4,5-c]quinoline-4-amine;

[0594]2-butyl-1-{2-[(4-fluorophenyl)sulfonyl]ethyl}1H-imidazo[4,5-c]quinoline-4-amine;

[0595]2-butyl-1-{2-[(1,1-dimethylethyl)sulfonyl]ethyl}1H-imidazo[4,5-c]quinoline-4-amine;

[0596]2-butyl-1-{2-[(1,1-dimethylethyl)thio]ethyl}1H-imidazo[4,5-c]quinoline-4-amine;

[0597]2-butyl-1-[2-(propylthio)ethyl]1H-imidazo[4,5-c]quinoline-4-amine;

[0598]2-butyl-1-{2-[(2-methylpropyl)sulfonyl]ethyl}1H-imidazo[4,5-c]quinoline-4-amine;

[0599]2-butyl-1-[2-(ethylsulfonyl)ethyl]1H-imidazo[4,5-c]quinoline-4-amine;

[0600] 2-butyl-1-[2-(ethylthio)ethyl]1H-imidazo[4,5-c]quinoline-4-amine;

[0601]2-butyl-1-[2-(methylsulfonyl)ethyl]1H-imidazo[4,5-c]quinoline-4-amine;

[0602]2-methyl-1-[6-(methylsulfonyl)hexyl]1H-imidazo[4,5-c]quinoline-4-amine;

[0603] 1-[5-(phenylsulfonyl)pentyl]1H-imidazo[4,5-c]quinoline-4-amine;

[0604]2-trifluoromethyl-1-[5-(methylsulfonyl)pentyl]1H-imidazo[4,5-c]quinoline-4-amine;

[0605]2-methoxyethyl-1-[5-(phenylsulfonyl)pentyl]1H-imidazo[4,5-c]quinoline-4-amine;

[0606]2-ethyl-1-[4-(pyrimidin-2-ylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0607]2-ethyl-1-[4-(pyrimidin-2-ylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0608]2-methyl-1-[4-(methylsulfonyl)butyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine;

[0609]2-methyl-1-[5-(methylsulfonyl)pentyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine;

[0610]2-methyl-1-{5-[(1-methylethyl)sulfonyl]pentyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine;

[0611]2-methyl-1-{4-[(4-fluorophenyl)sulfonyl]butyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine;

[0612]2-methyl-1-{4-[(1,1-dimethylethyl)sulfonyl]butyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine;

[0613]2-ethoxymethyl-1-[4-(pyrimidin-2-ylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0614]2-propyl-1-[4-(pyrimidin-2-ylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0615]2-propyl-1-[3-(pyrimidin-2-ylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0616]2-propyl-1-[5-(pyrimidin-2-ylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;

[0617]2-ethoxymethyl-1-[3-(pyrimidin-2-ylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine;and

[0618]2-ethoxymethyl-1-[5-(pyrimidin-2-ylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine,

[0619] and their pharmaceutically acceptable salts.

Cytokine Induction in Human Cells

[0620] An in vitro human blood cell system is used to assess cytokineinduction. Activity is based on the measurement of interferon and tumornecrosis factor (α) (IFN and TNF, respectively) secreted into culturemedia as described by Testerman et. al. In “Cytokine Induction by theImmunomodulators Imiquimod and S-27609”, Journal of Leukocyte Biology,58, 365-372 (September, 1995).

Blood Cell Preparation for Culture

[0621] Whole blood from healthy human donors is collected byvenipuncture into EDTA vacutainer tubes. Peripheral blood mononuclearcells (PBMC) are separated from whole blood by density gradientcentrifugation using Histopaque®-1077. Blood is diluted 1:1 withDulbecco's Phosphate Buffered Saline (DPBS) or Hank's Balanced SaltsSolution (HBSS). The PBMC layer is collected and washed twice with DPBSor HBSS and resuspended at 4×10⁶cells/mL in RPMI complete. The PBMCsuspension is added to 48 well flat bottom sterile tissue culture plates(Costar, Cambridge, Mass. or Becton Dickinson Labware, Lincoln Park,N.J.) containing an equal volume of RPMI complete media containing testcompound.

Compound Preparation

[0622] The compounds are solubilized in dimethyl sulfoxide (DMSO). TheDMSO concentration should not exceed a final concentration of 1% foraddition to the culture wells. The compounds are generally tested atconcentrations ranging from 30-0.014 μM.

Incubation

[0623] The solution of test compound is added at 60 μM to the first wellcontaining RPMI complete and serial 3 fold dilutions are made in thewells. The PBMC suspension is then added to the wells in an equalvolume, bringing the test compound concentrations to the desired range(30-0.014 μM). The final concentration of PBMC suspension is 2×10⁶cells/mL. The plates are covered with sterile plastic lids, mixed gentlyand then incubated for 18 to 24 hours at 37° C. in a 5% carbon dioxideatmosphere.

Separation

[0624] Following incubation the plates are centrifuged for 10 minutes at1000 rpm (˜200×g) at 4° C. The cell-free culture supernatant is removedwith a sterile polypropylene pipet and transferred to sterilepolypropylene tubes. Samples are maintained at −30 to −70° C. untilanalysis. The samples are analyzed for interferon (a) by ELISA and fortumor necrosis factor (a) by ELISA or IGEN Assay.

Interferon (a) and Tumor Necrosis Factor (α) Analysis by ELISA

[0625] Interferon (a) concentration is determined by ELISA using a HumanMulti-Species kit from PBL Biomedical Laboratories, New Brunswick, N.J.Results are expressed in pg/mL.

[0626] Tumor necrosis factor (α) (TNF) concentration is determined usingELISA kits available from Biosource International, Camarillo, Calif.Alternately, the TNF concentration can be determined by Origen® M-SeriesImmunoassay and read on an IGEN M-8 analyzer from IGEN International,Gaithersburg, Md. The immunoassay uses a human TNF capture and detectionantibody pair from Biosource International, Camarillo, Calif. Resultsare expressed in pg/mL.

[0627] The table below lists the lowest concentration found to induceinterferon and the lowest concentration found to induce tumor necrosisfactor for each compound. A “*” indicates that no induction was seen atany of the tested concentrations. Cytokine Induction in Human CellsExample Lowest Effective Concentration(μM) Number Interferon TumorNecrosis Factor 1 0.12 0.12 2 0.12 0.37 3 0.04 0.12 4 0.01 0.01 5 0.010.04 6 3.33 10 7 3.33 10 8 10 * 9 3.33 3.33 10 1.11 1.11 11 0.01 0.12 120.12 10 13 0.12 3.33 14 3.33 10 15 0.04 * 16 0.01 0.04 17 0.01 0.04 180.01 0.12 19 0.04 0.37 20 0.04 0.37 21 0.12 0.37 22 0.37 1.11 23 3.33 1024 0.12 0.37 25 0.37 3.33 26 0.04 0.37 27 3.33 10 28 0.01 0.37 29 0.123.33 30 0.37 3.33 31 0.04 0.12 32 0.12 0.12 33 3.33 10 34 0.37 3.33 351.11 3.33 36 1.11 1.11 37 0.37 1.11 38 0.37 1.11 39 0.04 0.04 40 0.010.01 41 0.37 0.37 42 0.12 0.12 43 0.014 0.37 44 1.11 10 45 0.37 1.11 460.12 0.37 47 0.37 3.33 48 0.014 0.12 49 0.37 1.11 50 0.37 1.11 51 0.121.11 52 0.37 1.11 53 0.04 0.37 54 0.37 1.11 55 0.12 1.11 56 0.37 0.37 571.11 1.11 58 1.11 1.11 59 0.01 0.04 60 0.37 0.37 61 0.04 0.12 62 0.120.37 63 0.04 0.04 64 0.12 0.12 65 0.01 0.04 66 0.12 0.12 67 0.01 0.04 680.014 0.12 69 1.11 1.11 70 0.01 0.01 71 30 *

What is claimed is:
 1. A compound of the formula (I):

wherein: X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-; Z is —S—, —SO—,or —SO₂—; R₁ is selected from the group consisting of: -alkyl; -aryl;-heteroaryl; -heterocyclyl; -alkenyl; —R₄-aryl; —R₄-heteroaryl;—R₄-heterocyclyl; R₂ is selected from the group consisting of:-hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl;-alkyl-Y-alkyl; -alkyl-Y-alkenyl; -alkyl-Y-aryl; and -alkyl or alkenylsubstituted by one or more substituents selected from the groupconsisting of: —OH; -halogen; —N(R₃)₂; —CO—N(R₃)₂; —CO—C₁₋₁₀ alkyl;—CO—O—C₁₋₁₀ alkyl; —N₃; -aryl; -heteroaryl; -heterocyclyl; —CO-aryl; and—CO-heteroaryl; each R₃ is independently H or C₁₋₁₀ alkyl; R₄ isalkylene or alkenylene; Y is —O— or —S(O)₀₋₂—; n is 0 to 4; and each Rpresent is independently selected from the group consisting of C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen and trifluoromethyl; or apharmaceutically acceptable salt thereof.
 2. A compound of claim 1wherein Z is —S—.
 3. A compound of claim 1 wherein Z is —SO₂—.
 4. Acompound of claim 1 wherein R₁ is -alkyl.
 5. A compound of claim 4wherein R₁ is -methyl.
 6. A compound of claim 1 wherein R₁ is aryl.
 7. Acompound of claim 1 wherein R₁ is heteroaryl.
 8. A compound of claim 1wherein X is —(CH₂)₂₋₆—.
 9. A compound of claim 1 wherein R₂ is H.
 10. Acompound of claim 1 wherein R₂ is -alkyl-O-alkyl.
 11. A compound ofclaim 1 wherein R₂ is -alkyl.
 12. A compound selected from the groupconsisting of:2-butyl-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-[4-(phenylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;1-[2-(phenylthio)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;1-[4-(phenylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-methyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-ethyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-hexyl-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-(2-methoxyethyl)-1-[5-(methylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-[5-(methylsulfinyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-[3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine;and2-butyl-1-[3-(phenylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine;or a pharmaceutically acceptable salt thereof.
 13. A compound of theformula (II)

wherein: X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-; Z is —S—, —SO—,or —SO₂—; R₁ is selected from the group consisting of: -alkyl; -aryl;-heteroaryl; -heterocyclyl; -alkenyl; —R₄-aryl; —R₄-heteroaryl; and—R₄-heterocyclyl; R₂ is selected from the group consisting of:-hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl;-alkyl-Y-alkyl; -alkyl-Y-alkenyl; -alkyl-Y-aryl; and -alkyl or alkenylsubstituted by one or more substituents selected from the groupconsisting of: —OH; -halogen; —N(R₃)₂; —CO—N(R₃)₂; —CO—C₁₋₁₀ alkyl;—CO—O—C₁₋₁₀ alkyl; —N₃; -aryl; -heteroaryl; -heterocyclyl; —CO-aryl; and—CO-heteroaryl; each R₃ is independently H or C₁₋₁₀ alkyl; R₄ isalkylene or alkenylene; Y is —O— or —S(O)₀₋₂—; n is 0 to 4; and each Rpresent is independently selected from the group consisting of C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen and trifluoromethyl; or apharmaceutically acceptable salt thereof.
 14. A compound of claim 13wherein Z is —S—.
 15. A compound of claim 13 wherein Z is —SO₂—.
 16. Acompound of claim 13 wherein R₁ is -alkyl.
 17. A compound of claim 16wherein R₁ is -methyl.
 18. A compound of claim 13 wherein R₁ is aryl.19. A compound of claim 13 wherein R₁ is heteroaryl.
 20. A compound ofclaim 13 wherein X is —(CH₂)₂₋₆—.
 21. A compound of claim 13 wherein R₂is H.
 22. A compound of claim 13 wherein R₂ is -alkyl-O-alkyl.
 23. Acompound of claim 13 wherein R₂ is -alkyl.
 24. A compound selected fromthe group consisting of:1-[5-(methylsulfonyl)pentyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine;2-methyl-1-[3-(methylthio)propyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-methyl-1-[3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-ethyl-1-[3-(methylthio)propyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-ethyl-1-[3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-methyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-methyl-1-[4-(methylsulfinyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-ethyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-ethyl-1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;1-[4-(methylsulfonyl)butyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-[4-(methylsulfinyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-methyl-1-[2-(methylthio)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-methyl-1-[2-(methylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-methyl-1-[4-(methylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-ethyl-1-[2-(methylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;1-[2-(methylsulfonyl)ethyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-{4-[(2,4-difluorophenyl)thio]butyl}-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-{4-[(2,4-difluorophenyl)sulfonyl]butyl}-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-[4-(ethylsulfonyl)butyl]-1H-imidazo[4,5-c]quinoline-4-amine;2-butyl-1-{4-[(1,1-dimethylethyl)thio]butyl}-1H-imidazo[4,5-c]quinoline-4-amine;2-butyl-1-{4-[(4-fluorophenyl)thio]butyl}-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-{4-[(4-fluorophenyl)sulfonyl]butyl}-1H-imidazo[4,5-c]quinolin-4-amine;2-ethyl-1-{4-[(1-methylethyl)thio]butyl}-1H-imidazo[4,5-c]quinoline-4-amine;1-{4-[(3,5-dichlorophenyl)thio]butyl}-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine;1-[4-(cyclopentylsulfonyl)butyl]-2-ethyl-1H-imidazo[4,5-c]quinoline-4-amine;1-{4-[(3,5-dichlorophenyl)sulfonyl]butyl}-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine;1-[4-(cyclohexylthio)butyl]-2-ethyl-1H-imidazo[4,5-c]quinoline-4-amine;1-[4-(butylthio)butyl]-2-ethyl-1H-imidazo[4,5-c]quinoline-4-amine;1-{4-[(4-chlorophenyl)thio]butyl}-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine;1-[4-(butylsulfonyl)butyl]-2-ethyl-1H-imidazo[4,5-c]quinoline-4-amine;2-ethyl-1-{4-[(4-fluorophenyl)thio]butyl}-1H-imidazo[4,5-c]quinolin-4-amine;2-ethyl-1-{4-[(1-methylethyl)sulfonyl]butyl}-1H-imidazo[4,5-c]quinoline-4-amine;2-ethyl-1-[4-(ethylthio)butyl]-1H-imidazo[4,5-c]quinoline-4-amine;2-ethyl-1-[4-(ethylsulfonyl)butyl]-1H-imidazo[4,5-c]quinoline-4-amine;1-[4-(cyclohexylsulfonyl)butyl]-2-ethyl-1H-imidazo[4,5-c]quinoline-4-amine;2-butyl-1-{2-[(1-methylethyl)sulfonyl]ethyl}-1H-imidazo[4,5-c]quinoline-4-amine;2-butyl-1-[2-(phenylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinoline-4-amine;2-butyl-1-{2-[(4-fluorophenyl)sulfonyl]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-{2-[(1,1-dimethylethyl)sulfonyl]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-{2-[(1,1-dimethylethyl)thio]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-[2-(propylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinoline-4-amine;2-butyl-1-[2-(propylthio)ethyl]-1H-imidazo[4,5-c]quinoline-4-amine;2-butyl-1-{2-[(2-methylpropyl)sulfonyl]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-{2-[(2-methylpropyl)thio]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-[2-(ethylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinoline-4-amine;2-butyl-1-[2-(ethylthio)ethyl]-1H-imidazo[4,5-c]quinoline-4-amine;2-butyl-1-[2-(methylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-methyl-1-[6-(methylsulfonyl)hexyl]-1H-imidazo[4,5-c]quinolin-4-amine;1-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;1-[5-(methylsulfonyl)pentyl]-2-(trifluoromethyl)-1H-imidazo[4,5-c]quinolin-4-amine;2-(2-methoxyethyl)-1-[5-(phenylsulfonyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-ethyl-1-[4-(pyrimidin-2-ylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-ethyl-1-[4-(pyrimidin-2-ylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;2-methyl-1-[4-(methylsulfonyl)butyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine;2-methyl-1-[5-(methylsulfonyl)pentyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine;2-methyl-1-{4-[(1-methylethyl)sulfonyl]butyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine;2-methyl-1-{4-[(4-fluorophenyl)sulfonyl]butyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine;and2-methyl-1-{4-[(1,1-dimethylethyl)sulfonyl]butyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine;or a pharmaceutically acceptable salt thereof.
 25. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1 and a pharmaceutically acceptable carrier.
 26. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 12 and a pharmaceutically acceptable carrier. 27.A method of inducing cytokine biosynthesis in an animal comprisingadministering a therapeutically effective amount of a compound of claim1 to the animal.
 28. The method of claim 27 wherein the cytokine isIFN-α.
 29. A method of treating a viral disease in an animal comprisingadministering a therapeutically effective amount of a compound of claim1 to the animal.
 30. A method of treating a neoplastic disease in ananimal comprising administering a therapeutically effective amount of acompound of claim 1 to the animal.
 31. A method of inducing cytokinebiosynthesis in an animal comprising administering a theraputicallyeffective amount of a compound of claim 12 to the animal.
 32. The methodof claim 31 wherein the cytokine is IFN-α.
 33. A method of treating aviral disease in an animal comprising administering a therapeuticallyeffective amount of a compound of claim 12 to the animal.
 34. A methodof treating a neoplastic disease in an animal comprising administering atherapeutically effective amount of a compound of claim 12 to theanimal.
 35. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 13 and a pharmaceuticallyacceptable carrier.
 36. A method of inducing cytokine biosynthesis in ananimal comprising administering a therapeutically effective amount of acompound of claim 13 to the animal.
 37. The method of claim 36 whereinthe cytokine is IFN-α.
 38. A method of treating a viral disease in ananimal comprising administering a therapeutically effective amount of acompound of claim 13 to the animal.
 39. A method of treating aneoplastic disease in an animal comprising administering atherapeutically effective amount of a compound of claim 13 to theanimal.
 40. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 24 and a pharmaceuticallyacceptable carrier.
 41. A method of inducing cytokine biosynthesis in ananimal comprising administering a therapeutically effective amount of acompound of claim 24 to the animal.
 42. The method of claim 41 whereinthe cytokine is IFN-α.
 43. A method of treating a viral disease in ananimal comprising administering a therapeutically effective amount of acompound of claim 24 to the animal.
 44. A method of treating aneoplastic disease in an animal comprising administering atherapeutically effective amount of a compound of claim 24 to theanimal.
 45. A compound of the formula (III):

wherein: X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-; R₂ is selectedfrom the group consisting of: -hydrogen; -alkyl; -alkenyl; -aryl;-heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; -alkyl-Y-alkenyl;-alkyl-Y-aryl; and -alkyl or alkenyl substituted by one or moresubstituents selected from the group consisting of: —OH; -halogen;—N(R₃)₂; —CO—N(R₃)₂; —CO—C₁₋₁₀ alkyl; —CO—O—C₁₋₁₀ alkyl; —N₃; -aryl;-heteroaryl; -heterocyclyl; —CO-aryl; and —CO-heteroaryl; each R₃ isindependently H or C₁₋₁₀ alkyl; Y is —O— or —S(O)₀₋₂—; n is 0 to 4; andeach R present is independently selected from the group consisting ofC₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen and trifluoromethyl; or apharmaceutically acceptable salt thereof.
 46. A compound of the formula(IV):

wherein: X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-; Z is —S—, —SO—,or —SO₂—; R₁ is selected from the group consisting of: -alkyl; -aryl;-heteroaryl; -heterocyclyl; -alkenyl; —R₄-aryl; —R₄-heteroaryl; and—R₄-heterocyclyl; R₂ is selected from the group consisting of:-hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl;-alkyl-Y-alkyl; -alkyl-Y-alkenyl; -alkyl-Y-aryl; and -alkyl or alkenylsubstituted by one or more substituents selected from the groupconsisting of: —OH; -halogen; —N(R₃)₂; —CO—N(R₃)₂; —CO—C₁₋₁₀ alkyl;—CO—O—C₁₋₁₀ alkyl; —N₃; -aryl; -heteroaryl; -heterocyclyl; —CO-aryl; and—CO-heteroaryl; each R₃ is independently H or C₁₋₁₀ alkyl; R₄ isalkylene or alkenylene; Y is —O— or —S(O)₀₋₂—; n is 0 to 4; and each Rpresent is independently selected from the group consisting of C₁₋₁₀;alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen and trifluoromethyl; or apharmaceutically acceptable salt thereof.
 47. A compound of claim 1wherein Z is —SO—.
 48. A compound of claim 13 wherein Z is —SO—.